Gullapalli, 2009, Soft Gelatin Capsules

REVIEW
Soft Gelatin Capsules (Softgels)

RAMPURNA PRASAD GULLAPALLI
Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, California 94080
Received 13 December 2009; revised 15 February 2010; accepted 19 February 2010

Published online 5 April 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22151
ABSTRACT: It is estimated that more than 40% of new chemical entities (NCEs) coming out of
the current drug discovery process have poor biopharmaceutical properties, such as low aqueous
solubility and/or permeability. These suboptimal properties pose significant challenges for the
oral absorption of the compounds and for the development of orally bioavailable dosage forms.
Development of soft gelatin capsule (softgel) dosage form is of growing interest for the oral
delivery of poorly water soluble compounds (BCS class II or class IV). The softgel dosage form
offers several advantages over other oral dosage forms, such as delivering a liquid matrix
designed to solubilize and improve the oral bioavailability of a poorly soluble compound as a unit
dose solid dosage form, delivering low and ultra-low doses of a compound, delivering a low
melting compound, and minimizing potential generation of dust during manufacturing and
thereby improving the safety of production personnel. However, due to the very dynamic
nature of the softgel dosage form, its development and stability during its shelf-life are
fraught with several challenges. The goal of the current review is to provide an in-depth
discussion on the softgel dosage form to formulation scientists who are considering developing
softgels for therapeutic compounds. 2010 Wiley-Liss, Inc. and the American Pharmacists Association
J Pharm Sci 99:41074148, 2010
Keywords: softgel; soft gelatin capsule; formulation; encapsulation; poorly soluble; bioavail-
ability; cross-linking; dissolution; physical stability; chemical stability
INTRODUCTION NCEs coming out of the combinatorial chemistry and

HTS technologies have been thought to belong to this
Oral absorption of a compound can be influenced by a category.4 Poor aqueous solubility has been identified
variety of factors, such as the physicochemical as the single largest physicochemical challenge for
properties, formulation, and dose of the compound the oral absorption of compounds and almost
and the physiology and pathology of the gastro- inevitably leads to their lower oral bioavailabilities
intestinal tract (GIT). Regardless of other factors, it is from the conventional dose forms.3
reasonable to conclude that the compound must be in Traditional approaches to enhance the absorption
the solution form or solubilized form in the GIT to of a compound relate to improving its solubility and
diffuse into and across the enterocytes lining the rate of dissolution in the GIT fluids. These approaches
intestinal lumen.1,2 The advent of combinatorial include using a form of the compound with optimum
chemistry and high throughput screening (HTS) aqueous solubility, for example, salt form,57 amor-
has resulted in the identification of many highly phous form,8,9 prodrug form,10 nanosizing,1113 or
potent new chemical entities (NCEs) that usually employing a vehicle in which the compound is soluble
have less than desirable physicochemical properties, and remain solubilized upon contact with the GIT
that is, high molecular weight, high lipophilicity aqueous environment.8,14
(log P), and low aqueous solubility.3 More than 40% of The least complex way to present a compound to the
GIT for absorption is to administer the compound as a
solution or solubilized form, thereby removing any
The contents of this article represent the efforts and views of the
author in his personal and professional capacity and do not neces- dissolution rate-limiting step in the absorption
sarily represent the views of Elan Pharmaceuticals, Inc. and/or its process.2 As the compound is already in solution at
affiliates. the site of absorption, it could yield a faster, uniform,
Correspondence to: Rampurna Prasad Gullapalli (Telephone:
914-316-4935; Fax: 650-877-7461; E-mail: RampurnaL@gmail.com) and enhanced absorption. Occasionally, nonaqueous
Journal of Pharmaceutical Sciences, Vol. 99, 41074148 (2010) (organic) vehicles are employed to solubilize poorly
2010 Wiley-Liss, Inc. and the American Pharmacists Association water soluble compounds for oral and parenteral
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 10, OCTOBER 2010 4107
4108 GULLAPALLI
use.15 Use of the nonaqueous vehicles in oral formulation and manufacturing components on the
products may be complicated by many factors. First, stability, dissolution, and bioavailability of the softgel
some nonaqueous vehicles, such as dimethylforma- dosage form. This review will be limited to only
mide (DMF) and dimethyl sulfoxide (DMSO), may softgels prepared from gelatin and will not address
have substantial solubilizing capacity for many softgels prepared from nongelatin material.
compounds. However, such vehicles are not pharma-
ceutically acceptable. Second, some vehicles, though
pharmaceutically acceptable, may not exert sufficient SOFTGEL MANUFACTURING PROCESS
solubilizing action to be of any practical value for
some compounds unless the dose is low. Otherwise, The manufacturing process for the production of
the volume of the vehicle required cannot be readily softgels is the rotary die process, invented by
contained in a convenient dose unit. Third, it is also Scherer,2529 in which a molten mass of a gelatin
possible that precipitation of the compound from the sheath (shell) formulation at 57608C is fed from a
solution may follow administration when the solubi- reservoir onto two separate rotating cool casting
lized compound encounters the aqueous environment drums (cooling drums) to form two spaced flat sheets
in the GIT, resulting in little or no absorption or ribbons of gelatin in a semi-molten state. Two tone
enhancement. softgels may be produced by utilizing two separate
When a compound demonstrates sufficient solubi- reservoirs of different color gelatin masses, each
lity in a pharmaceutically acceptable nonaqueous supplying one of the two ribbons for the cooling
vehicle, soft gelatin capsules may be ideal to deliver drums. These flat ribbons are extracted from the
the solution as a solid dosage form. Soft gelatin cooling drums and are fed around rollers that
capsules (SGC), also referred to as softgels or lubricate them, usually with fractionated coconut
soft elastic capsules (SEC), have gained popularity oil (e.g., Miglyol1 812, Sasol; Captex1 355, Abitec)/
in delivering therapeutic compounds solubilized or lecithin blend, and then brought together at a
suspended in nonaqueous vehicles. A softgel is a one- convergent angle into the nip of a pair of roller dies
piece, hermetically sealed soft gelatin shell contain- that include opposing die cavities. The lubrication
ing a solution, a suspension, or a semisolid, referred to step is necessary to avoid the sticking of ribbons
as fill formulation, fill material, or fill. Softgels offer together and to other machine parts. The typical
many advantages over other conventional oral dosage speed at which a gelatin ribbon is drawn into an
forms, including improving swallowbility, masking encapsulation station is limited to around 2.5 cm/s
odors and unpleasant taste, protecting the encapsu- due to the limitation of a conventional encapsulation
lated compound against oxygen and light, and able to machine. However, higher speeds may be achieved
readily dissolve in the gastric juices of the GIT. The with some modifications to the encapsulation
absorption of poorly soluble compounds encapsulated machine.30 A fill formulation, to be encapsulated,
in softgels may also be higher compared to that from flowing from its own reservoir through a tube under
other conventional dosage forms not only due to the gravity, is fed into a positive displacement pump.
solubilization of the compounds in the fill formulation Accurately metered volumes of the fill formulation
but also due to the fill excipient induced inhibition of are injected from a wedge (heated to 37408C) into the
P-glycoprotein-mediated drug efflux and reduced space between gelatin ribbons as they pass between
enzyme-catalyzed degradation of the compound in the cavities on the die rolls. As the ribbons meet on the
the lumen of the GIT.1624 Softgels also offer the rim of the opposing die cavities, the bottom lips of the
advantage of accurately delivering therapeutic cavities initially seal, forming what is referred to as
agents that require ultra-low doses (e.g., cardiac lower seam. The fill formulation is then injected
glycosides, vitamin D analogs). precisely into the semi formed softgel. The softgel
One of the major challenges in the development of halves are then sealed together (forming the upper
the softgel dosage form is that the system is very seam) by the application of heat and pressure. The
dynamic in terms of (a) the physical migration of heated wedge provides enough heat to the gelatin
components between the shell and the fill and the ribbons that aids in the sealing of the two-halves of a
shell and the external environment, and (b) the softgel. It is extremely critical to avoid entrapment of
occurrence of physical and chemical interactions fill material within the upper seam, a concern during
within and between the shell and fill components. the encapsulation of highly viscous, viscoelastic, and
It is critical to understand these intricacies to develop stringy materials (e.g., povidone, surfactants). Such
a softgel product that is stable and provides desired entrapment potentially results in the formation of
in vitro and in vivo characteristics. This review article weak seams and subsequent leakage of a softgel
deals with the various aspects of softgel dosage form, product. This phenomenon is not a concern in the case
including selection of fill and shell compositions and of the lower seam, as it has already formed before the
manufacturing process and the influence these injection of the fill material into the softgel.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 10, OCTOBER 2010 DOI 10.1002/jps
SOFT GELATIN CAPSULES 4109
The softgels, severed around each of the die eners, and preservatives. The gel mass is prepared by
cavities, are ejected by the continuous rotation of initially mixing water and plasticizer(s) with gelatin
the dies and are carried on a conveyer into a tumble granules in a suitable reactor (kettle) to form a fully
dryer. The part of the gelatin sheath that is severed hydrated fluff at room temperature. The material is
from the segments forming the softgels (referred to as then melted thoroughly at high temperatures (90
net) is then collected for recovery and recycling of 958C) under vacuum (29.5 inch Hg) with slow mixing
gelatin31,32 or for disposal. Photographs of softgel until a clear gel is obtained. The gel mass is then
encapsulating machine and tumble dryer are shown transferred into electrically heated holding tanks and
in Figure 1. During the encapsulation, a series of in- kept at 57608C for encapsulation.33 If the gel
process checks such as ribbon thickness (Vernier formulation requires an opacifier, the opacifier is
Calipers), seam thickness (microscopy), fill weights, initially dispersed and wetted thoroughly in glycerin
and shell weights are performed at regular intervals. before its addition to the molten gel mass. Dispersion
The various steps involved in the manufacturing of a and wetting of the opacifier is usually accomplished
softgel product can be grouped into five components: in a manufacturing setting by mixing it with glycerin
(a) gel mass, (b) fill formulation, (c) ribbons for in rotating drums or using drum mixers for extended
encapsulation, (d) drying, and (e) finishing. The periods. Other ingredients, such as colorants, flavors,
critical parameters in each manufacturing compo- and preservatives, may be added and mixed at high
nent and their effects on a softgel product are listed in speeds. Gelatin undergoes depolymerization when
Table 1. the gel mass is stored at high temperatures, resulting
in a reduction of the gel strength and viscosity with
Gel Mass time.34 Thus, the temperature and time, to which the
gel mass is exposed, need to be carefully monitored
A gel mass (shell formulation) is usually prepared
and controlled throughout the encapsulation process.
from gelatin, plasticizer(s), water, and other minor
The gel mass is checked for clarity, color, consistency,
additives such as opacifiers, colorants, flavors, sweet-
and moisture content before encapsulation to insure
that the gel will run properly on the encapsulation
machine.
Fill Formulation
A fill formulation for encapsulation into softgels can
be a solution, liquid-in-liquid dispersion, or a solid-in-
liquid suspension. Fill formulations are prepared
using standard procedures employed in pharmaceu-
tical solution, suspension, and semisolid manufactur-
ing. Fill formulations after compounding are
deaerated thoroughly under vacuum to eliminate
any of the entrapped air in the formulation. The
deaeration is a critical step in the manufacturing of a
softgel product that affects not only the fill viscosity,
blend uniformity, fill weight uniformity, and thus
content uniformity during manufacturing, but also
the physical and chemical stability of the finished
softgel product during its shelf-life. Smaller scale
batches of fill formulations can be deaerated in a
pressure resistant stainless steel container under
vacuum. Larger scale fill formulations are typically
vacuum transferred into pressure resistant stainless
steel tanks and further deaerated under vacuum (e.g.,
FrymaKoruma Vacuum Deaerator). For highly vis-
cous fill formulations, deaeration process can be aided
by moderate mixing with or without the use of heat.
The length of deaeration of a fill formulation is
influenced by a variety of factors, such as the
Figure 1. Photographs of Softgel Manufacturing Equipment. composition (e.g., lipophilic vs. hydrophilic, solution
(A) Encapsulating Machine; (B) Tumble Dryer (Courtesy of Pii vs. suspension, presence or absence of viscosifiers and
(Pharmaceutics International, Inc.)). surfactants), amount, and viscosity of the fill mate-
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 10, OCTOBER 2010
4110 GULLAPALLI
Table 1. Critical Parameters in a Softgel Product Manufacturing
Manufacturing Component Parameter Effects
Gel Mass Composition: gelatin type and Gel rheology, ribbon integrity and
concentration, plasticizer(s) type and strength, seam cutting and strength,
concentration, moisture content softgel drying time, softgel hardness
Process: gel aging and brittleness, oxygen and volatile
temperature and time solute permeability, physical
and chemical stability
Fill Formulation Composition: type (hydrophilic vs. Fill rheology, blend and content
lipophilic), solution versus suspension, uniformity, fill weight variation, seam
particle size, morphology integrity (due to fill trapping), softgel
(suspensions), viscosifiers, surfactants drying time, softgel hardness and
Process: mixing, temperature, inert brittleness, physical and
environment (nitrogen blanketing, chemical stability
yellow lights), deaeration
Encapsulation Cooling drums and dies speeds, Fill weight variation, seam
cooling drums temperature, wedge thickness and strength,
temperature, ribbon thickness, production rate, drying time
softgel size
Drying Primary drying (tumble/rotary) Fill moisture content, shell moisture
conditions, Secondary drying content, softgel hardness and
(tray) conditionstemperature brittleness, case hardening, shell
and humidity, drying rate cross-linking, dissolution
(air flow), drying time
Finishing Sizing, polishing, printing, Product quality, physical and
inspection, packaging chemical stability
(container-closure)
rial, deaeration temperature, and the type of deaera- through the gap uniform along the entire length of the
tion equipment used. gap thereby resulting in the formation of a ribbon
The fill formulation may be maintained at up to a with uniform thickness across its entire width and
maximum of 35378C at the time of encapsulation to length. The thickness of the ribbon can be controlled
facilitate the encapsulation process and higher through controlling the flow of gel mass that can be
temperatures should be avoided as they could readily accomplished by increasing or decreasing
interfere with the sealing of softgels. Fill formulations the speed of the rotating roll. The rotating roll in the
which are viscoelastic (stringy), shear sensitive hopper mechanism also helps in removing macro-
(shear-thickening or dilatant material), and solidify scopic air bubbles from the viscous gel mass before it
during the encapsulation process, can pose significant passes through the gap thus enhancing the quality of
challenges during the manufacture of softgels. Such the film deposited on the cooling drum. The spreader
fill material may be encapsulated into softgels by boxes control the flow of gel mass onto the cooling
continuous heating of the material in its reservoir and drums to a ribbon thickness within 10% of set
in the conveying tubing to higher temperatures until specification. The wet ribbon thickness may vary
it reaches the dosing pump where it is cooled to lower from 0.022 inches to 0.045 inches, with larger softgel
temperatures just before it reaches the wedge for sizes requiring thicker shell to accommodate the
encapsulation.35 higher structural strength required during their
manufacture.33
Ribbons for Encapsulation
The gel mass is typically at about 57608C when it
During the manufacture of a softgel product using comes into contact with the cooling drums. The
the rotary die process, the gel mass is spread onto temperature of the cold air used to cool the drums is
the cooling drums to form ribbons with the aid of typically about 13148C.33 The air cooling process
metering devices known as spreader boxes. A may be inefficient in cooling the drums uniformly
spreader box, as invented by Scherer,36 consists of across their entire surface.37 US patent 7,078,05437
a hopper having an elongated slot at its bottom and a proposes that the surface of the cooling drums and the
rotating roll (spindle) spaced between the two edges of gelatin sheaths spread over them may be better and
the slot to provide a gap through which the molten gel more evenly cooled by the cooling drums that use a
mass is extruded by the rotation of the roll. The liquid coolant (e.g., water) than by the ones that use
mechanism allows the volume of the gel mass passing air coolant. The gelatin sheaths containing propylene
glycol as the plasticizer are substantially tackier than typically contains water somewhere from 30 to
those containing glycerol or sorbitol as the plasticizer 40% w/w.34,3941 During the encapsulation and
and thus difficult to extract from the cooling drums. subsequent primary drying processes, depending
The use of a liquid coolant in the cooling drums may on the nature of the fill formulation encapsulated,
result in such gelatin sheaths containing propylene the fill may pick up water anywhere from zero
glycol sticking less strongly to the cooling drums and percent to 20% w/w. During the secondary drying
thus may be easily removed from them. Another process, the fill may loose some water leaving an
advantage of using a liquid coolant over cold air in amount anywhere from zero percent to 8% w/w in
cooling the drums is that the cooling process the fill. The rate and extent of this water migration
temperature can be altered and controlled more processes in both directions are influenced by the
precisely with the former to meet the cooling nature of the fill formulation, nature of the shell
requirements for various gel mass compositions. formulation, thickness of the shell, and size of the
For example, the temperature of the coolant water softgels. The dynamics of water migration during
can be altered precisely from about 20228C, optimal the softgel drying processes is depicted in Figure 2.
operational temperature for a gel mass in the absence The moisture content of the fill in a softgel is
of propylene glycol, to about 18208C and 16188C, typically measured using a KarlFisher apparatus.
optimal operational temperatures for gel masses The softgel is cut open at the seam with a knife and
containing 10% and 21% propylene glycol, respec- the fill is collected into a syringe. The syringe is
tively, as the plasticizer.37 capped tightly to prevent any moisture transfer
between the fill and the surroundings until measure-
Drying
ments are completed. The moisture content of the
Softgels formed at the encapsulating machine are shell is measured using a loss on drying (LOD)
highly flexible due to excessive moisture content of apparatus. The softgel is cut open at the seam with a
the starting gel mass.34,3841 Softgels originating from knife and its fill contents are drained. The shell is
the encapsulating machine undergo a primary short then given a quick wash in a suitable organic solvent,
time, low intensity drying process followed by a
secondary longer time, high intensity drying process.
Softgels are initially tumble dried in a hollow drum(s)
with perforated walls (Fig. 1B) (primary or rotary
drying process).38 Dry air is continuously pumped
through the rotating drum(s) at an air temperature
lower than 358C. The warm air being blown onto the
softgels may penetrate the shell and cause it to dry
from the inside by moving the water outward to the
surface of the softgel. The warm temperature also
helps to keep the gel in semi-fluid state that promotes
further sealing of softgels. Sometimes adsorbent
towels are used in the tumble dryer to remove any
lubricant carried over during the encapsulation
process. By the time the softgels exit this tumble
drying process, a significant portion of water from
the shell has been removed into the fill and/or into the
environment.
After the softgels exit the tumble dryer (primary
or rotary drying process), they are spread on to
trays. The final drying phase (secondary or tray
drying process) of the softgels is accomplished by
inserting the stacks of trays into a drying tunnel
maintained at controlled temperature (21248C) and Figure 2. Dynamics of Water Migration during Softgel Drying
Process Water migration patterns during drying of a softgel product
low relative humidity (2030%) conditions.42 The containing a typical (A) PEG 400 fill formulation; (B) mixed medium
time for the secondary drying process for softgels chain mono-, di-, and triglycerides fill formulation with or without
may vary from few hours to few days, depending on an added surfactant(s); and (C) medium chain triglycerides (MCT)
the nature of the fill formulation (i.e., hydrophilic or long chain triglycerides (LCT) fill formulation. Yellow inner
core represents fill formulation and brown exterior represents
vs. lipophilic), nature of the shell formulation (e.g.,
gelatin shell. Numerical values represent approximate percent
type and concentration of plasticizer(s)), thickness water content, w/w. ( ) Water migration from shell to fill, ( ) water
of the shell, and size of the softgels. The shell migration from fill to shell, and ( ) water migration from shell to
formulation at the time of encapsulation process environment.
4112 GULLAPALLI
such as petroleum ether, and wiped clean of any acceptable moisture levels and may still contain up to
remaining fill contents with a paper towel before the 10% water after drying.
measurements are initiated. Softgels permitted to come to moisture equilibrium
The hardness of a softgel is measured using a at the controlled temperature (21248C) and relative
Bareiss hardness tester. Photographs of the Bareiss humidity (2030%) conditions of the secondary drying
digital hardness testers are presented in Figure 3. process are considered dry.42 The shell material of
The instrument operates by compressing the softgel such dry softgels usually contains 816% w/w water
under test for a brief period (e.g., 20 s) between a depending on the specific gelatin shell formulation
plunger attached to a load cell and a platform which is used. The range of water content between 7.6% and
automatically raised. To test a softgel for its hardness, 14% in gelatin was hypothesized to correspond to the
it is placed horizontally on the platform with its seam water sorbed by the polar groups in gelatin or the
contour aligned parallel to the platform and the structural water, which is bound with the proteins by
platform then raised enough so that the softgel is in hydrogen bonding both inside and outside the helical
contact with both the platform and the plunger. fragments.44,45 The fill material of the dry softgels
During the test, the platform rises automatically and usually contains as high as 610% w/w water for a
the load cell indicator displays the value of the simple polyethylene glycol 400 based formulation to
resistance of the softgel to the compressive force. less than 0.5% w/w water for a medium chain
After the test period, the resistance value is displayed triglyceride (MCT) or a long chain triglyceride
in Newtons (N) and represents the hardness of the (LCT) oil based formulation (Fig. 2).
softgel under test.41 After the softgels are dry, they may be subjected
Drying is a dynamic process and the process to an additional step, known as stress relieving step or
continues until the gelatin shell returns to its tempering step, to improve the overall quality of a
equilibrium moisture content, which is in the range softgel product.42 The step involves a change in the
of 1015% w/w.43 Softgels containing a lipophilic fill conditions of temperature and relative humidity from
generally dry faster than those containing a hydro- the secondary drying step and is accomplished at a
philic fill and typically reach equilibrium shell temperature range of 32388C and a relative humid-
moisture within 24 h. If water migrates into the fill ity range of 3560%. The stress relieving step can
from the shell extensively, more typical of polyethy- take place in the same tunnel as the secondary drying
lene glycol fills, it needs to migrate back out until the step, and thus requires no additional equipment or
fill moisture content reaches equilibrium with the labor. The step is intended to remove any dimples
moisture content of the shell for the optimal physical present in the shell and any bubbles present in the fill.
stability of a softgel product. The polyethylene glycol In addition, the step also reduces the dimensional
based fills may take from 7 to 10 days to reach standard deviation thereby resulting in more dimen-
sionally uniform batches of softgels.42 The dimen-
sional uniformity of a softgel product is typically
measured by the standard deviation in the lengthwise
and widthwise measurement of an oblong softgel or
the diameter wise of a round softgel.
The rate and extent of softgel drying are the critical
processing parameters that should be carefully
controlled. Removal of too much water may result
in hard, brittle softgels that have a higher propensity
to develop cracked shells and/or require a longer time
for dissolution. On the other hand, insufficient drying
may result in very soft softgels that become tacky and/
or tightly stick to each other with time. If the softgels
are subjected to rapid drying conditions, such as high
drying temperature, very low relative humidity, and/
or high airflow, the product may under go a
phenomenon referred to as case hardening.46 Case
hardening occurs when the exterior surface of the
softgel dries very rapidly and forms a temporary seal
Figure 3. Photographs of the Bareiss Hardness Testers A.
Analogue hardness tester (Model HP) with the stand (Model BS that prevents further egress of moisture from the fill
61); B. Digital hardness tester (Model HPE II) with the stand and shell. The hardness of such a softgel increases
(Model BS 61 II). (Courtesy of Heinrich Bareiss Pruefgeraetebau temporarily reaching an acceptable value. However,
GmbH.) http://www.bareiss.de/english/produkte/pruefgeraete_ the excess moisture entrapped within the fill and
start.html.
shell migrates slowly during storage, resulting in a
very soft softgel product. An acceleration of the drying promising in improving its bioavailability. A vehicle
process can also potentially lead to considerable for the development of a softgel fill formulation should
changes in the structure and properties of the shell ideally satisfy the following criteria:
material. Though the presence of a plasticizer in the
shell formulation may mitigate these deleterious Pharmaceutically acceptable for oral use.
effects of the faster drying conditions to some extent, Sufficient solubilizing capacity to dissolve a
the drying process should be carefully controlled to given dose in a small volume.
minimize its effects on the thermal and mechanical Yield a fill formulation that is stable and compa-
properties of the shell material.47 tible with gelatin shell material.
Yield a fill formulation that is easier to compound
Finishing and encapsulate.
Prevent precipitation of the solubilized com-
After drying, the softgels are sorted (sized),48
pound within the softgel product during its man-
polished, printed,49 and inspected for their quality.
ufacturing and shelf-life, and upon contact with
The softgels are then packaged into suitable contain-
the aqueous environment in vitro (dissolution)
ers, typically of low density polyethylene (LDPE)
and in vivo (GIT).
bags, high density polyethylene (HDPE) bottles, or
blisters. The recommended storage conditions for the
Vehicles suitable for encapsulation into softgels can
softgels include a temperature range of 15308C and a
be broadly classified into two groups:
relative humidity of not more than 50%.43,50 When
stored under these conditions, the equilibrium
A. Hydrophilic vehicles.
moisture content of the shell material and oxygen
B. Lipophilic vehicles (lipid based fill formulations).
permeability through the material are minimal, thus
improving the stability of the softgel product.43
The readers are directed to the review by Wilkinson Hydrophilic Vehicles
and Hom51 to obtain an extensive understanding of
the design of a softgel manufacturing facility and Hydrophilic vehicles for softgel fill formulations
equipment used in the softgel manufacturing. include polyethylene glycols (e.g., PEG 400, PEG
600), methoxypolyethylene glycols (e.g., MPEG 350,
MPEG 550), diethyleneglycol monoethyl ether
FILL FORMULATIONS (Transcutol1), tetrahydrofurfurylalcohol polyethy-
lene glycol (Glycofurol), propylene carbonate, N-
Types of fill formulations that can be delivered using methyl-2-pyrrolidone (NMP), polyoxyethylenepoly-
softgel delivery system include: solutions, suspen- oxypropylene copolymers (Poloxamers), propylene
sions, emulsions, microemulsions, self-emulsifying glycol, glycerin, ethyl alcohol, and water. The use of
drug delivery systems (SEDDS), and self-microemul- propylene glycol, glycerin, and water is restricted to
sifying drug delivery systems (SMEDDS). The con- less than 10% of the total fill formulation, as these
sistency of a fill formulation may vary from a free vehicles can also act as plasticizers for the gelatin
flowing liquid (e.g., Rocaltrol1 Softgels, Roche shell.54 Similarly, use of lower molecular weight
Pharmaceuticals; Hectorol1 Softgels, Genzyme Cor- polyethylene glycols (e.g., PEG 200, PEG 300) in the
poration) to a thick suspension (e.g., Zantac1 Soft- fill formulations is limited due to their ability to
gels, GlaxoSmithKline; Prometrium1 Softgels, diffuse into the shell and thereby act as gelatin
Solvay Pharmaceuticals). In the case of self-micro- plasticizers.5557 The extent of diffusion of a poly-
emulsifying (SMEDDS) and self-emulsifying ethylene glycol from the fill into the shell decreases
(SEDDS) formulations, a compound dissolved in a with an increase in its molecular weight.40,41 The use
lipophilic vehicle containing one or more emulsifiers of volatile components, such as ethyl alcohol, in the fill
and cosolvents, forms a microemulsion (droplet size formulations is limited due to their ability to rapidly
0.15 mm) when the ratio of emulsifier to lipid is high diffuse through the shell material, and carrying out
(>1) or a fine emulsion (droplet size >0.15 mm) when other fill components in the process.54,5860
the ratio is <1, respectively, upon dilution with
aqueous fluids in vitro or in vivo.52
Pros and Cons of Use of Polyethylene Glycols in Softgels
Compounds belonging to class II and class IV of
the Biopharmaceutics Classification System (BCS) Polyethylene glycols, due to their ability to be
show extremely low aqueous solubility throughout miscible with aqueous fluids in all proportions and
the physiological pH range, resulting in low and dissolve many pharmaceutical compounds at the
inconsistent bioavailability.53 However, when such a same time make them ideal vehicles for the delivery of
compound demonstrates enhanced solubility in a many poorly soluble compounds in softgels. Com-
nonaqueous vehicle, softgel delivery system may be pounds with poor bioavailability and considerable
4114 GULLAPALLI
individual variability in the absorption have been solubility 10 mg/mL), from PEG 400 solution was
shown to provide exceptionally high bioavailability shown to diminish in fasted beagle dogs from
and reduced inter-subject variability in plasma 49.6 19.7% to 5.2 1.8% when the dose was
concentrations when dosed as solutions or suspen- increased from 100 to 350 mg.70 The reduced bioa-
sions in polyethylene glycols.6167 However, while vailability of the compound from PEG 400 solution at
polyethylene glycols often may have high solubilizing the higher dose was attributed to the extent of its
power for some poorly water soluble compounds, the precipitation in the aqueous fluids of the GIT.
high affinity of these vehicles for water can poten- A blend of two or more of polyethylene glycols of
tially lead to the precipitation of dissolved compounds various molecular weights may sometimes be used
when the formulation comes into contact with an either to modify the consistency of a fill formulation
aqueous environment in vitro or in vivo.6872 The and thereby prevent settling of material in a
solvent capacity of a hydrophilic solvent, such as suspension formulation66 or to control the rate of
polyethylene glycol and propylene glycol, for a release of an encapsulated compound from a softgel
hydrophobic compound has been shown to fall product.73 Such a formulation can be easily com-
approximately logarithmically as the formulation is pounded at a temperature slightly higher than the
diluted with water.69,71 Serajuddin et al.,69 for melting point of the higher molecular weight
example, demonstrated a sharp reduction in the polyethylene glycol used in the blend and then
solubility of a test compound in PEG 400 from 250 mg/ brought to a semisolid form by lowering the
g to about 1.5 mg/g with an increase in water content temperature during its encapsulation. The formula-
from 0% to 50% in the formulation (Fig. 4). Gross tion remains solidified in the softgel at ambient
crystallization of the solubilized test compound was temperature and thereby minimize the settling and
also observed when the PEG 400 based solution migration of any of the fill components. Such a
formulation was encapsulated into softgels, due to the semisolid fill formulation may also have an added
migration of water from the shell into the fill. This advantage of providing effective deterrent to poten-
water-prone crystallization process may result in the tial intravenous drug abuse on account of its high
improvements in the bioavailability of a compound a viscosity making injection at ambient temperature
dose-dependent phenomenon, that is, higher percent difficult.66 The rate of release or the potential for
bioavailability at lower doses and diminished drug abuse of an encapsulated compound from such
percent bioavailability as the dose increases.70,72 a semisolid matrix may be further controlled by
For example, the oral bioavailability of a poorly including a gelling agent, such as an organic
soluble investigational compound, DMP 323 (aqueous polymeric material (e.g., cellulose polymers, acrylic
acid polymers)73,74 or an inorganic salt (e.g., calcium
acetate)75 in the formulation.
Absorption of Polyethylene Glycols

Orally administered polyethylene glycols of a lower
molecular weight (e.g., PEG 200, PEG 300, PEG 400)
are well absorbed in the GIT and are mostly (>90%)
excreted unchanged in urine and feces in human
subjects.76 Absorption studies in human volunteers
have shown that about one-third of the orally
administered PEG 400 is excreted in the urine and
the remainder of the dose is likely to pass through the
gut intact and subsequently eliminated in the
feces.77,78 In addition, more than 75% of PEG 400
found in the urine is excreted within the first 4 h after
oral administration, implying that absorption of the
polymer predominantly occurs from the small intes-
tine.78 Lower molecular weight polyethylene glycols
are hypothesized to be absorbed through the intest-
inal epithelium by passive diffusion and solvent
drag.79 The oral absorption of a polyethylene glycol
Figure 4. Influence of Added Water on the Solubility of Poorly has been shown to decrease with an increase in its
Soluble a-pentyl-3-(2-quinolinylmethoxy) benzene methanol in molecular weight (e.g., fraction absorbed: 100% for
PEG 400 at 208C (Insert-Semilogarithmic Plot) (Adopted from PEG 200 and PEG 300, 10% for PEG 4000, 0% for
Serajuddin et al.69). PEG 6000).8084
Influence of PEG 400 on GIT Motility and Absorption of agent (i.e., counter-ion; neutralizing agent). For
Compounds example, the solubility of acidic compounds (e.g.,
ibuprofen, naproxen, indomethacin, acetaminophen)
Mechanistically, PEG 400 was shown to have a
in polyethylene glycols can be enhanced through
concentration-dependent effect on gastrointestinal
partial ionization of these compounds with a hydro-
motility and transit.78,85,86 Radiolabeled studies have
xide ion species (e.g., sodium hydroxide, potassium
suggested that the mean gastric residence time
hydroxide, ammonium hydroxide). Whereas, the
(MGRT) of an aqueous vehicle containing PEG 400
solubility of basic compounds (e.g., thioridazine,
was similar to that of an aqueous vehicle free from
cimetidine, ranitidine, nifedipine) can be enhanced
PEG 400 (MGRT of about 20 min). The mean small
through partial ionization with a hydronium ion
intestinal transit time (MSITT), in contrast, was
species (e.g., hydrochloric acid, hydrobromic acid,
shown to decrease with an increase in the concentra-
sulfuric acid, an organic acid). For amphoteric
tion of PEG 400 in the aqueous vehicle (MSITT of
compounds, either hydroxide ion or hydronium
153 min at 10 g PEG 400 dose in aqueous vehicle
ion sources may be utilized to effect enhanced
versus 236 min for PEG 400 free aqueous vehicle).85
solubilization.
The mechanism behind the influence of PEG 400 on
The solubility enhancing techniques employed
the intestinal transit of a coadministered liquid
by Yu et al.,90 Morton et al.,91 and Shelley et al.92
formulation was attributed to the incomplete absorp-
result in a softgel fill formulation containing a
tion of the polymer from the intestine and the
compound as a mixture of its unionized form (free
resulting polymer induced osmotic activity. PEG
acid or base) and its corresponding ionized form (i.e.,
400 would probably increase the luminal fluid volume
salt form). When used these neutralization (counter
via the retention of water, which in turn stimulates
ion) techniques to obtain a highly concentrated
intestinal motility and hence transit.87 Since the
solution of a compound, it is essential to keep the
small intestine is the primary site for absorption of
apparent pH of the final fill formulation at least
many compounds, a reduction in the contact time
between 2.5 and 7.5. At pH values below 2.5, gelatin is
with this region of the GIT could potentially impact
hydrolyzed94 causing leakage of the softgel, whereas
the bioavailability of orally administered compounds.
at pH values above 7.5, gelatin may be either
The absorption of low permeability compounds (i.e.,
hydrolyzed94 or tanned (i.e., cross-linked) resulting
BCS class III and class IV) is likely to be the most
in decreased solubility of the gelatin shell.33 In
susceptible to changes in intestinal residence time.88
addition, the ionizing agents used as solubility
PEG 400 at higher levels (2.5 g), for example, was
enhancers contain a highly reactive species which
shown to reduce the small intestinal residence time of
may react adversely with other ingredients present in
a liquid formulation, resulting in a significant
the softgel.95 The use of a highly reactive species, such
reduction in the oral bioavailability of ranitidine,
as hydroxide ion, may be substituted with a milder
dissolved within.78,85,86 However, at a lower concen-
and relatively neutral salt, such as ammonium
tration (1 g), PEG 400 was shown to significantly
acetate,96 an alkali metal acetate,92 or a combination
enhance the absorption of ranitidine, possibly via
of alkali metal acetate/lactate,97 in enhancing the
modulation of intestinal permeability.86 PEG 400 was
solubility of acidic compounds that is more compatible
also thought to have a significant impact on efflux
with the other softgel components.
process via P-gp transporter inhibition and metabo-
Alternately, the solubility of some compounds
lism of some drugs during their migration through
(e.g., acetaminophen, danazol, ibuprofen) in hydro-
the GIT.89
philic vehicles can also be improved significantly by
using povidone (polyvinylpyrrolidone, PVP) as a
Solubility Enhancers for Hydrophilic Vehicles
solubility enhancer.55,56,67,98 Unlike the solubility
It is desirable to produce a highly concentrated enhancing techniques employed by Yu et al.,90
solution of a compound as it allows the encapsulation Morton et al.,91 and Shelley et al.,92 the use of
of a unit dose of the compound in a softgel that is povidone as a solubility enhancer results in a softgel
small enough to swallow easily and thus improving fill formulation containing a compound in its original
patient acceptance of the medication. Yu et al.,90 form that is very compatible with the other softgel
Morton et al.,91 and Shelley et al.92 invented components. In addition, as povidone is available in
methods for enhancing the solubility and producing a variety of molecular weights ranging from 2500 to
highly concentrated solutions for acidic, basic, and 3000000,99 the viscosity of a fill formulation can be
amphoteric compounds in hydrophilic vehicles sui- controlled through the selection of appropriate
table for filling softgels (referred to as enhanced molecular weight and concentration of the polymer
solubility system or ESS).93 These inventions allow without adversely affecting the solubility of dis-
the improvement in the solubility of some compounds solved compounds.98 An advantage of using a higher
in polyethylene glycols by 40400% using an ionizing amount of a lower molecular weight povidone as a
4116 GULLAPALLI
solubility enhancer is the reduction in the amount dissolved compound after dispersion in the aqueous
polyethylene glycol available in the fill formulation fluids. These formulations are referred to as type II
for any potential reactions with acidic compounds under LFCS. In contrast, a type I lipid formulation
such as ibuprofen free acid (e.g., esterification may include a hydrophilic surfactant (HLB > 12)
reactions), a well known disadvantage that results and/or a water soluble cosolvent (e.g., propylene
in the reduction of available ibuprofen in its free glycol, polyethylene glycol, ethyl alcohol) to increase
form.100 Use of povidone of a lower molecular weight the solvent capacity of the formulation for a
also yields a fill formulation of a lower viscosity and compound. These formulations are referred to as
thus improving the product manufacturability and type III under LFCS. A type IV formulation
dissolution characteristics.98 comprises predominantly of a hydrophilic cosolvent
and a surfactant, and with or without minimal oil
Lipophilic Vehicles (Lipid Based Fill Formulations) components.
Lipophilic vehicles for softgel fill formulations include The digestion (lipolysis) of a triglyceride within
free fatty acids (e.g., oleic acid), fatty acid esters of the GIT by the pancreatic lipase/colipase complex
hydroxyl compounds, such as ethyl alcohol, propylene into amphiphilic diglycerides, monoglycerides, and
glycol, glycerin, sorbitol, sucrose, polyethylene gly- free fatty acids can enhance the dissolution rate of a
cols, and polyethoxylated fatty acid esters. The fatty poorly soluble compound coadministered with the
acid composition of these esters may vary from short vehicle (the subject will be discussed in more detail
chain (SC, <C8) to medium chain (MC, C8-C10) to in Lipid Digestion and Absorption and Influence on
long chain (LC, C12). Absorption of Compounds Section). However, the
poor miscibility of the undigested triglyceride with
the GIT aqueous environment may lead to highly
Classification of Lipid Based Fill Formulations
variable gastric emptying and/or dispersion into an
Lipid based fill formulations generally comprise of a emulsion which in turn, can result in variable
compound dissolved or suspended in one or more absorption of the compound from the GIT.106 The
excipients consisting of triglycerides (TG), mixed dispersibility of the triglyceride in the GIT fluids can
glycerides, surfactants, and cosolvents. The simplest be enhanced by including a surfactant in the
lipid formulation is one in which a compound is formulation. Interestingly, Lacy et al.,107 using
dissolved in a digestible oil, usually a long chain in vitro digestion experiments, demonstrated that
triglyceride (LCT, e.g., vegetable oil) or a medium the lipolysis of a triglyceride might be retarded by a
chain triglyceride (MCT, e.g., fractionated coconut hydrophilic surfactant (i.e., HLB >10) (e.g., Cremo-
oil). These formulations may be appropriate for phor RH 40, Cremophor EL, Polyoxyethylene
potent compounds and/or highly lipophilic com- sorbitan monooleate), typically used in the lipid
pounds (log P > 4) and require digestion of the based fill formulation for a poorly soluble compound
formulation before absorption.71,101,102 Some com- (type III formulation). Lacy et al.107 further demon-
pounds may have limited solubility in triglycerides strated that the inhibitory effect of a hydrophilic
or may yield lower bioavailability when dosed in surfactant on the in vitro lipolysis of a triglyceride
these formulations.103,104 The solvent capacity of could be countered substantially by the inclusion of a
triglyceride vehicles for some compounds may be lipophilic surfactant (i.e., HLB < 10) in the formula-
improved by blending them with other mixed tion. Some examples of such beneficial lipophilic
glycerides, that is, diglycerides (DG) and monogly- surfactants include, free fatty acids (e.g., oleic acid,
cerides (MG), and free fatty acids (FA). The linoleic acid, linolenic acid), mono- and/or di-glycer-
advantage of using these mixed glycerides is that ides (e.g., glyceryl mono- and di-caprylate/caprate,
these components are similar to the natural diges- distilled acetylated monoglycerides), sorbitan fatty
tion products of the triglycerides and do not interfere acid esters (e.g., sorbitan monolaurate, sorbitan
with the regular lipid digestion and absorption monooleate), and polyglycerol esters of fatty acids
processes. These triglyceride and mixed glycerides (e.g., polyglyceryl oleate).
formulations are referred to as type I under lipid Few examples of currently marketed lipid based
formulation classification system (LFCS), proposed formulations delivered using softgel technology are
by Pouton71,101,102 and Porter et al.105 The solubi- included in Table 2. The list includes such well
lization of a compound in a type I lipid formulation known products as Cyclosporine A (Sandimmune1
may sometimes be improved with the inclusion of a [type II] and Neoral1 [type III]; Novartis Pharma-
lipophilic surfactant (HLB < 12). This approach is ceuticals, Australia), Ritonavir (Norvir1; Abbott
used primarily to promote the emulsification of a Laboratories), Lopinavir/Ritonavir (Kaletra1; Abbott
formulation vehicle in the aqueous fluids of the GIT Laboratories), Saquinavir (Fortovase1; Roche Phar-
under gentle agitation. This type of lipid formulation maceuticals), Amprenavir (Agenerase1 [type IV];
is likely to retain its solvent capacity for the GlaxoSmithKline), Calcitriol (Rocaltrol1 [type I];
Table 2. Examples of Softgel Products with Their Fill Compositions and Dissolution Methods
Drug Product Information Fill Excipients Properties, Dissolution Method
Hydrophilic fills
Agenerase1, Amprenavir, 50 PEG 400, D-a-tocopheryl polyethylene HIV-protease inhibitor, MW 505.63,
and 150 mg, GlaxoSmithKline, glycol 1000 succinate (TPGS), Aq. Sol. 40 mg/mL, clog P 3.29306,
NDA 21-007 propylene glycol BCS Class II307
Softgel-introductory dosage form.
Amprenavir softgel product was
later reformulated into a tablet
formulation (Lexiva1, NDA 21-548)
containing its phosphate ester
prodrug, fosamprenavir calcium,
with improved aqueous solubility
Apparatus I at 50 rpm in 900 mL
of 0.1 N HCl at 37 0.58Ca
Targretin1, Bexarotene, PEG 400, polysorbate 20, povidone Antineoplastic, MW 348.48,
75 mg, Eisai/Ligand, K-90, butylated hydroxyanisole (BHA) Aq. Sol. insoluble
NDA 21-055 Softgel-introductory dosage form
Apparatus II at 50 rpm in
900 mL of 0.05 M phosphate
buffer, pH 7.5 containing 0.5%
hexadecyltrimethylammonium
bromide (HDTMA) at 37 0.58Ca
Lanoxicap1, Digoxin, 0.05, PEG 400, ethyl alcohol, Heart failure, cardiotonic, MW 780.94,
0.1, and 0.2 mg, GlaxoSmithKline, propylene glycol Aq. Sol. 10 mg/mL, BCS Class I308,309
NDA 18-118 More complete absorption of digoxin
from soft capsules and recommended
oral doses are only 80% of those for
tablets and elixir
Apparatus I at 120 rpm in 600 mL of
water (37 0.58C)b
Zarontin1, Ethosuximide, PEG 400 Anticonvulsant, MW 141.17, Aq. Sol.
250 mg, Pfizer, NDA 12-380 freely soluble
Softgel-introductory dosage form
phosphate buffer, pH 6.8 at 37 0.-
0.58Cc
VePesid1, Etoposide, 50 mg, PEG 400, glycerin, water, citric acid Antineoplastic, MW 588.56, Aq. Sol.
Bristol-Myers-Squibb, 0.20 mg/mL310
Apparatus II at 50 rpm in 900 mL
of acetate buffer, pH 4.5 at 37 0.-
0.58Cc
Advil1, ibuprofen, 200 mg, PEG 600, potassium hydroxide, Anti-inflammatory
Wyeth, NDA 20-402 water, (ibuprofen is present as MW 206.28, Aq. Sol. 10 mg/mL,
free acid/potassium salt) BCS Class II308,309
Initial launch as tablet (NDA 18-989);
softgel as line-extension
phosphate buffer, pH 7.2 at 37 0.-
0.58Ca
Ibuprofen Capsules, Ibuprofen, PEG 600, D-a-tocopheryl
200 mg, Banner Pharmacaps, polyethylene glycol 1000 succinate
Inc., NDA 21-472 (TPGS), povidone, (ibuprofen is
present as free acid)
Advil PM Liqui-Gels1, Ibuprofen PEG 600, potassium hydroxide, Anti-inflammatory/antihistaminic,
200 mg and, Diphenhydramine HCl water, (ibuprofen is present as sedative, hypnotic, MW 206.28 and
25 mg, Wyeth, NDA 21-393 free acid/potassium salt) 291.82, Aq. Sol. 10 mg/mL and
1 g/mL, BCS Class II308,309
Apparatus I at 100 rpm in 900 mL
of 200 mM phosphate buffer,
pH 7.2 at 37 0.58Ca
Aleve1, Naproxen sodium, 220 mg, PEG 400, propylene glycol, Anti-inflammatory,
Bayer HealthCare, NDA 21-920 povidone, lactic acid MW 252.24, soluble
(Continued)
4118 GULLAPALLI
Table 2. (Continued )
Initial launch as tablet (NDA 17-581;

as free acid); softgel as second-line
of 0.1 M phosphate buffer (pH 7.4),
at 37 0.58Cd
Procardia1, Nifedipine, 10 and PEG 400, glycerin, peppermint Antianginal, MW 346.33, Aq. Sol.
20 mg, Pfizer, NDA 18-482 oil, sodium saccharin 12 mg/mL, BCS Class II308,309,311
Softgel-introductory dosage form,
tablet as line-extension
(NDA 19-684; higher doses)
of SGF at 37 0.58Cc
Nimotop1, Nimodipine, 30 mg, PEG 400, glycerin, peppermint Vasodilator, MW 418.44, Aq. Sol.
Bayer HealthCare, NDA 18-869 oil, water 4 mg/mL, BCS Class II312
of water, containing 0.5% sodium
dodecyl sulfate at 37 0.58Ca
Hytrin1, Terazosin HCl, PEG 400, glycerin, povidone Benign prostatic hyperplasia (BPH),
1, 2, 5, and 10 mg, Abbott MW 459.92, Aq. Sol. 24.2 mg/mL
Laboratories, NDA 20-347 Initial launch as tablet (NDA 19-057);
Navelbine1, Vinorelbine tartrate, PEG 400, ethanol, glycerol, water NSCLC, breast cancer, multiple
20, 30, and 80 mg, Pierre myeloma, MW 1079.11, Aq.
Fabre, NDA 20-388 Sol. >1000 mg/mL
Lipophilic solution fills
One Alpha1, Alfacalcidol, Sesame oil, dl-alpha-tocopherol Renal osteodystrophy,
0.25 mg, 0.5 mg, and 1 mg, hyperparathyroidism,
LEO Pharma, Ex-US hypocalcaemia, rickets,
MW 400.64, Aq. Sol. insoluble
Rocaltrol1, Calcitriol, 0.25 mg Fractionated coconut oil, butylated Calcium regulator, MW 416.64,
and 0.5 mg, Roche Pharmaceuticals, hydroxyanisole (BHA), butylated Aq. Sol. insoluble
NDA 18-044 hydroxytoluene (BHT) Softgel-introductory dosage form
USP rupture testd
Hectorol1, Doxercalciferol, 0.5, 1, Fractionated coconut oil, ethyl alcohol, Antihyperparathyroidism, MW 412.65,
and 2.5 mg, Bone Care Int., butylated hydroxyanisole (BHA) Aq. Sol. insoluble
Inc., NDA 20-862 Softgel-introductory dosage form
USP rupture testd
Marinol1, Dronabinol, 2.5, 5, Sesame oil Anorexia, nausea, MW 314.46,
and 10 mg, Unimed and log P 3.78
Roxane, NDA 18-651
Apparatus II at 100/150 rpm in
500 mL of water, containing 10%
Labrasol (37 0.58C)a. Plus USP
rupture test,c,d
Avodart1, Dutasteride, 0.5 mg, Medium chain mono- and diglycerides, Benign prostatic hyperplasia (BPH),
GlaxoSmithKline, NDA 21-319 butylated hydroxytoluene (BHT) MW 528.53, Aq. Sol.<0.038 ng/mL,
log P 5.09
of 0.1 N HCl containing 2% sodium
dodecyl sulfate at 37 0.58Ca
Drisdol1, Ergocalciferol, 50000 Soybean oil Parathyroid disease, refractory
IU, Sanofi-Aventis, NDA 3-444 rickets, MW 396.65, Aq. Sol. insolu-
ble
USP disintegration testc
Claritin1, Loratadine, 10 mg, Caprylic/capric glycerides, Antihistamine, MW 382.88, Aq.
Schering-Plough, NDA 21-952 polysorbate 80, povidone Sol. insoluble
Initial launch as tablet (NDA 19-658);
(Continued)

1
Amitiza , Lubiprostone, 24 mg, Medium chain triglycerides Chronic idiopathic constipation,
Sucampo and Takeda, MW 390.46, Aq. Sol. insoluble
NDA 21-908
Zemplar1, Paricalcitol, 1, 2, Medium chain triglycerides, Antihyperparathyroidism, MW 416.64,
and 4 mg, Abbott Laboratories, ethyl alcohol, butylated Aq. Sol. insoluble, BCS Class IV
NDA 21-606 hydroxytoluene (BHT) Softgel-introductory dosage form
Fortovase1, Saquinavir, 200 mg, Medium chain mono- and diglycerides, HIV-protease inhibitor, MW 670.84,
Roche Pharmaceuticals, povidone, DL-a-tocopherol Aq. Sol. 2.2 mg/mL, log P 2.73, clog P
NDA 20-828 4.73, BCS Class IV305307
Fortovase1 softgel product was
replaced with tablet (Invirase1
500 mg) and powder filled HGC
capsule (Invirase1 200 mg)
formulations containing its
mesylate salt, with reduced
dosing (NDA 21-785 and NDA 20-6-
28)
of citrate buffer containing 0.582%
anhydrous dibasic sodium phosphate
and 1.67 g citric acid monohydrate
at 37 0.58Cc
Andriol1, Testosterone Castor oil, propylene glycol Hypogonadism, MW 456.70,
undecanoate, 40 mg, monolaurate Aq. Sol. insoluble
Organon, EX-US
Depakene1, Valproic acid, Corn oil Antiepileptic, MW 144.21, Aq. Sol.
250 mg, Abbott Laboratories, 1.3 mg/mL, BCS Class II309
of SIF TS without enzyme and with
monobasic sodium phosphate (inst-
ead of monobasic potassium phos-
phate)
and pH adjusted to 7.5 with 5 M so-
dium hydroxide; containing 0.5% s-
odium
dodecyl sulfate at 37 0.58Cc
Lipophilic suspension fills
Toctino1, Alitretinoin, 10 Refined soya-bean oil, partially Atopic dermatitis, MW 300.44,
and 30 mg, Basilea hydrogenated soya-bean oil, medium Aq. Sol. insoluble
Pharmaceutica AG, Ex-US chain triglycerides, yellow beeswax,
All-rac-a-tocopherol
Symmetrel1, Amantadine Rape seed oil, soybean lecithin, Infections, influenza, Parkinsons,
HCl, 100 mg, Novartis blend white beeswax and MW 187.71, Aq. Sol. freely soluble
Pharmaceuticals, Ex-US hydrogenated soya and vegetable oils
Lamprene1, Clofazimine, 50 Rapeseed oil, hydrogenated soybean Antileprosy, MW 473.40, Aq. Sol.
and 100 mg, Novartis oil, partially hydrogenated vegetable 0.49 mg/mL, log P 4.36, BCS Class
Pharmaceuticals, oils, propylene glycol, beeswax, II/IV307,313
NDA 19-500 butylated hydroxytoluene (BHT),
soybean lecithin, p-methoxy Softgel-introductory dosage form
acetophenone, sodium ethyl
paraben, sodium propyl paraben USP rupture testd
Accutane1, Isotretinoin, 10, 20, Soybean oil, beeswax, hydrogenated Antiachne, MW 300.44, log P 6.6117
and 40 mg, Roche Pharmaceuticals, soybean oil flakes, hydrogenated Softgel-introductory dosage form
NDA 18-662 vegetable oil, butylated hydroxyanisole Apparatus I at 100 rpm in 900 mL
(BHA), edetate disodium of 0.05 M potassium phosphate
dibasic buffer, pH 7.8 containing
0.5% lauryldimethylamine-oxide
(LDAO) at 37 0.58Ca
(Continued)
4120 GULLAPALLI

1
Glakay , Menatetrenone, 15 mg, L-Aspartic acid, carnauba wax, Osteoporosis, MW 444.65, Aq.
Eisai Co., Ex-US hydrogenated oil, ethyl Sol. insoluble
parahydroxybenzoate, propyl
parahydroxybenzoate, propylene
glycol esters of fatty acids,
glyceryl monooleate
Prometrium1, Progesterone, Peanut oil, lecithin Hormone, MW 314.46, Aq. Sol.
100 and 200 mg, Solvay/Schering, insoluble, log P 3.78305
NDA 19-781
USP rupture testd
Zantac1, Ranitidine HCl, 150 Medium chain triglycerides, Treatment of ulcers, MW 350.86,
and 300 mg, GlaxoSmithKline, mixed glycerides of long chain Aq. Sol. soluble
NDA 20-095 fatty acids (Gelucire1 33/01)
Withdrawn from market
of water at 37 0.58C
Self-emulsifying (SEDDS) and
self-microemulsifying (SMEDDS) fills
Sandimmune1, Cyclosporin Corn oil, ethyl alcohol, linoleoyl Immunosuppressant MW 1202.61,
A, 25, 50, and 100 mg, Novartis macrogolglycerides Aq. Sol. 40 mg/mL, LogP 2.92, BCS
Pharmaceuticals, NDA 50-625 Class IV305,314,315
Neoral1, Cyclosporin A, 25 and Corn oil-mono- and di-triglycerides, Apparatus II at 75 rpm in 500 mL (for
100 mg, Novartis Pharmaceuticals, ethyl alcohol, polyoxyl 40 25 mg dose) or 1000 mL (for 100 mg
NDA 50-715 hydrogenated-castor oil, propylene dose) of 0.1 N HCl containing 2 mg/
glycol, DL-a-tocopherol mL (for 25 mg dose) or 4 mg/mL (for
100 mg dose) of N,N-dimethydode-
cylamine N-oxide at 37 0.58Ca, plus
USP rupture test,c,d
Cyclosporine Capsules, Cyclosporin A, PEG 400, ethyl alcohol, D-a-tocopheryl
25 and 100 mg, Eon Labs Mfg., Inc., polyethylene glycol 1000 succinate
ANDA 65-017 (TPGS), polyoxyl 40 hydrogenated-
castor oil
Kaletra1, Lopinavir 133.3 mg, Oleic acid, polyoxyl 35 castor oil, HIV-protease inhibitor, lopinavir-MW
Ritonavir 33.3 mg, Abbott propylene glycol 628.80, Aq. Sol. 40 mg/mL, clog P 6.-
Laboratories, NDA 21-226 09, BCS Class IV306,307,316
Kaletra1 softgel product was
replaced with a tablet formulation
with increased drug loading
(strength200 mg/50 mg) and with
reduced food effects (NDA 21-906)
of 10 mM sodium phosphate mono-
basic solution containing 0.05 M
polyoxyethylene 10 lauryl ether,
pH 6.8 at 37 0.58Ca
Norvir1, Ritonavir, 100 mg, Oleic acid, ethyl alcohol, polyoxyl 35 HIV-protease inhibitor
Abbott Laboratories, NDA 20-659 castor oil, butylated hydroxytoluene MW 720.94, Aq. Sol. 1 mg/mL,
(BHT) clog P 4.94, BCS Class IV306,309,311
of 0.1 N HCl, containing 0.025 M
polyoxyethylene 10 lauryl ether
at 37 0.58Ca
Information on fill excipients was collected from label, prescription information, or available FDA approval packages; information on
indication, molecular weight (MW), and aqueous solubility was collected from The Merck Index, 2006 or otherwise referenced.
a
FDA Websitehttp://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm?PrintAll1.
b
British Pharmacopeia, 1998.
c
USP/NF Monographs.
d
US Pharmacopeia, 2009.
Roche Pharmaceuticals), and Isotretinoin (Accu- Lipid Digestion and Absorption and Influence on
tane1; Roche Pharmaceuticals). Absorption of Compounds
The consumption of a meal, particularly one contain-
ing a large quantity of lipids, stimulates a number of
Characteristics of Lipid Based Fill Formulations
physiological responses, including a reduction in
A type II formulation yields a broader particle size gastric transit (with no change in small intestinal
distribution in micron size upon aqueous dilution transit108), alterations in gastric pH, secretion of
(SEDDS), whereas a type III formulation yields a pancreatic enzymes, stimulation of biliary lipid
clear or almost clear dispersion with micron (SEDDS) release from the gallbladder, and promotion of
or submicron (SMEDDS) size distribution. A distinc- lymphatic transport.109111 The resultant release of
tion between type III and type II lipid formulations is biliary lipids, primarily bile salts, phospholipids, and
that the water soluble components in the former cholesterol, promotes the formation of a number of
formulation will tend to part from the oil during colloidal species in association with the digestion
dispersion and become dissolved in the aqueous (lipolysis) products from the triglyceride (e.g., digly-
phase. Pouton71 speculated that the forces involved cerides, monoglycerides, and fatty acids) within the
in this phase separation may be the driving force for small intestine.112,113 A prerequisite to the lipid
the emulsification of a type III formulation and coined absorption process is the micellar diffusion of these
the phrase diffusion and stranding to describe the lipid digestion products across the aqueous boundary
process. In contrast, the lipophilic surfactant in a type layer and then into the microclimate adjacent to the
II formulation would less likely disperse extensively intestinal membrane. Once in the enterocytes, fatty
into the aqueous phase and promote the emulsifica- acids and monoglycerides of carbon chain length more
tion of glycerides in the aqueous phase. The than 12 are combined with phospholipids/cholesterol
unfavorable consequence of type III and also type to form triglyceride, which packs into chylomicrons
IV formulations is that the dissolved compound may (0.050.75 mm) and enter the lymph system. Chylo-
be partially or completely precipitated when these microns are the major lipid transporting lipoproteins
formulations come in to contact with an aqueous in intestinal lymph and are composed primarily of a
environment in vitro or in vivo.70,103 The extent of triglyceride core which is stabilized in the aqueous
precipitation of a dissolved compound from these environment of the lymph by a surface coating of
formulations will ultimately depend on the aqueous phospholipids, cholesterol, and proteins.114 The
solubility of the compound and hydrophilicity of the phospholipids in chylomicrons are mainly of endo-
lipid formulation. Compounding the problem further, genous origin, the cholesterol derives from many
the precipitated compound can take on a variety of sources (diet, blood, digestive secretions, newly
forms including the amorphous form, crystalline synthesized in the enterocytes), and the triglycerides
form, and of varying particle size distributions contain both endogenous and exogenous fatty
depending upon the nature of the aqueous environ- acids.114,115 The lymphatic transport of a lipophilic
ment and the kinetic conditions that exist in the compound, via chylomicrons, may eventually be
GIT.24 It is essential to evaluate these properties determined by its solubility and partitioning into
in vitro during the selection of a softgel fill vehicle as the triglyceride core of the chylomicrons.116 Lipophi-
they could potentially impact the in vivo bioavail- lic compounds with (a) a high log P (>5), (b)
ability of a solubilized compound. For example, the significant solubility in LCT (50 mg/mL), and (c)
oral bioavailability of a poorly soluble investigational administered either in fed state or with an appro-
compound, WIN 54954, in fasted beagle dogs was priate lipid source in fasted state, are thought to
shown to be erratic and inconsistent when it was potentially gain direct access to the systemic circula-
administered as a solution in PEG 600-Polysorbate tion through the intestinal lymphatic transport,
80 solvent blend (type IV formulation).103 In contrast, resulting in the improved bioavailability of these
the plasma profiles of the compound were consistent compounds.116121 Compounds transported from the
when it was administrated as a type II formulation intestinal lumen by the intestinal lymph gain access
consisting of a MCT-ethoxylated glyceryl trioleate to the general circulation of the body at the junction of
blend. The erratic and inconsistent absorption of the the left internal jugular and left subclavian veins,
compound from the hydrophilic PEG formulation was thereby bypassing the hepatic system.116
attributed to its erratic and inconsistent precipitation Food intake, due to its affect on reduced gastric
in the GIT aqueous environment. Whereas, the transit, can increase the solubilization time and thus
improvement in the plasma profiles from the type the solubility of a poorly soluble compound in the
II formulation was attributed to the dispersion of stomach contents.108 The formation of the aforemen-
the triglyceride into fine emulsion droplets (diameter tioned mentioned colloidal species further aids in the
<3 mm) with the compound still dissolved within. solubilization of poorly soluble compounds in the GIT,
4122 GULLAPALLI
whereas the stimulation of lymphatic transport aids relatively increased contribution of the intestinal
in the improved absorption and reduced hepatic lymphatic transport (C18, 15.8% of dose > C810,
metabolism of these compounds. Even relatively 5.5% > C4, 2.22% > C0, 0.34%) to the overall absorp-
small quantities of LCT (e.g., 2 g) are thought to be tion of the compound. In a concurrent study, after oral
capable of stimulating the gall bladder contraction administration of the three types of triglycerides
and thereby elevating intestinal bile salts, phospho- (LCT, MCT, and SCT) to the lymph cannulated,
lipids, and cholesterol levels. The extent of this fasted rats, the amount of LCT present in the lymph
stimulatory response appears to increase as the was three- and ninefold, respectively, higher after
quantity of LCT administered increases.110 This LCT administration compared to that after MCT and
effect is a likely contributor to the ability of LCT SCT administration. This was thought to be due to
based formulations to reduce food effects and to the stimulatory effect of exogenously administered
enhance the oral bioavailability of some poorly soluble LCT on the secretion and lymphatic transport of
compounds. In contrast, administration of similar endogenous LCT, and the effect was hypothesized
quantities of MCT was shown to have relatively to diminish with a decrease in the chain length of
limited effects on the gallbladder contraction and the exogenously administered triglyceride (i.e.,
would not stimulate appreciable increase in the LCT > MCT > SCT).121,128,129 The lipophilic com-
intestinal concentration of biliary-derived lipids.110 pounds administered in LCT were suggested to be
In addition, fatty acids with carbon chain length less transported in the lymph in association with the
than 12 directly enter the portal blood leading to the resynthesized exogenously provided LCT present in
liver and then into the systemic circulation, thus the core of the lymph lipoproteins (i.e., chylomicrons),
circumventing the lymphatic transport mechanism. as opposed to in association with the more polar,
Thus, fatty acids with medium chain length are endogenously derived surface components such as
transported primarily by the portal blood, whereas phospholipid and protein.121 Though, these and many
ones with longer chain length are incorporated other studies demonstrated that LCT vehicles could
primarily into the chylomicrons and transported in enhance lymphatic uptake and yield relatively high
the lymph.114 An understanding of how lipids of concentrations of a lipophilic compound in the lymph,
varying chain lengths of fatty acids could influence it should not be overlooked that the overall compound
the mode of transportation and absorption of dis- uptake may be some 50150 times greater than that
solved compounds across the GIT provides valuable observed to occur via the lymphatics due to the
guidance to the formulation scientist in the selection limited lymph flow.117,118
of an appropriate lipid in the softgel fill formulation. The relative oral bioavailability of another
The absorption of lipophilic compounds in fasted poorly soluble compound, danazol (aqueous solubility
state was shown to be significantly higher from a 0.42 mg/mL at 378C; LCT-soybean oil solubility
formulation containing even a small amount of LCT 4.8 mg/mL at 378C; log P 4.5; BCS Class II130), in
than that from a formulation containing either lipids fasted beagle dogs from various formulations was also
of MCT or no lipids.121126 For example, Fischler shown to be in the order of LCT solution LCT-
et al.122 demonstrated a higher relative oral bioavail- SMEDDS > MCT-SMEDDS > micronized powder.126
ability and more rapid absorption of clomethiazole in In a concurrent in vitro digestion studies, danazol was
fasting healthy volunteers when it was administered observed to precipitate more extensively upon aqu-
as a softgel containing arachis oil based formulation eous dilution of the MCT-SMEDDS formulation
compared to a tablet formulation. The oral bioavail- compared to the LCT-SMEDDS formulation. The
ability of clomethiazole was also shown to increase bioavailability of danazol from the micronized powder
with increase of coadministered oil amount. In was significantly higher in the fed state compared to
another example, the bioavailability of the poorly that in the fasted state. Importantly, the relative
soluble anti-malarial compound, halofantrine (aqu- bioavailability of danazol from the LCT solution and
eous solubility <0.1 mg/mL; LCT solubility >50 mg/ LCT-SMEDDS in the fasted state was shown to be
mL; log P 8.5) solubilized in LCT and administered statistically indistinguishable from that of the
in fasted state was shown to be similar to that from micronized powder administered in the fed state.
of a lipid-free formulation administered in-fed These studies clearly demonstrate that an appro-
state.125,127 In lymph cannulated, fasted rats, the priate lipid formulation may be capable of achieving
calculated relative systemic exposure of orally the same positive food effect as the postprandial
administered halofantrine (i.e., sum of plasma avail- administration of a poorly soluble compound.
ability and lymphatic transport) was shown to Another extensively studied example of lipidic
increase with an increase in the fatty acid chain formulation is of cyclosporin A (aqueous solubility
length of the coadministered lipid (C18-LCT, 22.7% of 40 mg/mL; log P 2.92; BCS Class IV), which is supplied
dose > C810-MCT, 19.2% > C4-SCT, 15.2% > C0-tri- as a self-emulsifying oil solution (SEDDS) under
glyceride free, 6.4%).121 This was attributed to the the trade name Sandimmune1 (Novartis Pharma-
ceuticals) and as a microemulsion preconcentrate temperature (e.g., 258C, 378C) and analyzing the
(SMEDDS) under the trade name Neoral1 (Novartis supernatant, collected after centrifugation and filtra-
Pharmaceuticals). Sandimmune1 cyclosporine fill tion of the suspension, using an appropriate analy-
formulation comprises of corn oil (LCT), linoleoyl tical method.104,117,130 The method is modified when
macrogolglycerides (Labrafil1 M-2125-CS), and ethyl developing a solution fill formulation for softgel
alcohol (Tab. 2), which forms a coarse emulsion on encapsulation to take the water migration processes
dispersion into an aqueous media.131 The triglyceride occur in a softgel into account.139 The solubility of a
excipients in Sandimmune1 formulation require compound in a solvent is determined by dissolving
further lipolysis in vivo into diglycerides, monogly- increasing amounts of the compound in a fixed
cerides, and free fatty acids, for efficient release amount of the solvent. A portion of the solution at
and absorption of cyclosporine.52,132,133 In contrast, each concentration is mixed with water to mimic
Neoral1 cyclosporine fill formulation comprises of water migration and retention processes occur in a
corn oil mono- and di-glycerides, polyoxyl 40 hydro- softgel. The highest concentration of the compound at
genated castor oil (Cremophor1 RH 40), propylene which no precipitation is observed in the presence of
glycol, ethyl alcohol, and dl-a-tocopherol (Tab. 2), water at the equilibrium level is assumed to be the
which spontaneously forms a microemulsion with a equilibrium solubility of the compound in the softgel
droplet size below 100 nm when introduced into an compatible vehicle. When evaluating the solubility of
aqueous media.131 The improved dispersion charac- a compound in a semisolid or a solid vehicle at room
teristics and presence of the rapidly absorbable mono- temperature, solutions of varying concentrations of
and di-glycerides, which would not require further the compound are prepared at a temperature above
lipolysis in vivo (thus circumventing the lypolytic the melting point of the vehicle. The solutions are
process) have been suggested to be responsible for the then allowed to solidify at room temperature. The
increased bioavailability and reduced inter- and solid solutions are observed periodically under a
intra-subject variability of cyclosporine from Neoral1 polarized microscope for the presence of any crystals
formulation.134,135 The bioavailability of cyclosporine of the compound.69
from Neoral1formulation, for example, was shown to A hypothetical example of a softgel solution fill
be significantly higher (174239%), dose propor- formulation development for a compound is illu-
tional, and free from food effects with reduced inter- strated in Table 3. In this example, the solubility of
and intra-subject variability compared to that the compound in a neat vehicle is evaluated at
from Sandimmune1formulation.134,135 In addition, increments of 10 mg/g (e.g., maximum solubility
the potential inhibitory effect of the polyethoxylated 50 mg/g). Depending on the type of vehicle (i.e.,
surfactant (i.e., Cremophor RH 40) in Neoral1 PEG, mixed medium chain glycerides, MCT, or LCT),
formulation on CYP3A and P-gp efflux functional- the solutions are mixed with water at two levels that
ities18,2022,136 may also contribute to the increase the fill solutions are expected to be exposed to during
in bioavailability of cyclosporine from Neoral1 the encapsulation, drying phase, and subsequent
formulation.105 equilibrium (Fig. 2). These solutions are placed at
It is important to bear in mind that the influence of room temperature (RT) and accelerated physical
the type of formulation and the type of lipid used in stability conditions (e.g., 48C and 208C) for about
the formulation on the bioavailability can vary from a month. Solutions that do not show any crystal-
one compound to other and with the amount of dose lization, when observed visually and under a micro-
administered. Grove et al.,137,138 for example, demon- scope, at a water level (higher) representing the
strated that the bioavailability of poorly soluble primary drying phase within 24 h and at a water level
seocalcitol in rats was similar from a simple oil (lower) representing the equilibrium phase for a
solution or a SMEDDS and was not influenced by the month at all stability conditions are considered for
chain length of the lipid used in the formulations. The further development (e.g., 20 mg/g in the example).
bioavailability of another poorly soluble investiga- It is, however, worth mentioning two aspects of water
tional compound, LAB687 (aqueous solubility migration and its influence on physical stability of a
0.17 mg/mL; log P 4.7), was shown to be similar from dissolved compound in softgels. First, though a
a lipid formulation (corn oil glycerides, Cremophor compound dissolved in a vehicle for encapsulation
RH 40, ethyl alcohol, and propylene glycol) and a PEG may exhibit precipitation upon exposure to a higher
3350-polysorbate 80 formulation in fasted beagle water level during the primary drying phase, the
dogs.8 compound may re-dissolve in the vehicle upon
removal of the excess water during the secondary
Fill Formulation Development
drying phase. Thus, it may be meaningful to fill the
Typically, solubility determinations are carried out by solution formulation into empty soft gelatin capsules
equilibrating a suspension containing an excess (referred to as air-fills) and monitor the precipitation-
amount of a compound in a solvent at a constant re-dissolution phenomenon during cycling of the
4124 GULLAPALLI
Table 3. Experimental Design for the Development of a Hypothetical Softgel Solution Fill Formulation
Water Mimicking Primary Drying Mimicking Equilibrium

Content Before
Fill Vehicle Encapsulation (%) Amount of Water to be Added (%)
a, 317
PEG based 12 16 8
Mixed MC glycerides 0.15a, 318 6 4
MCT/LCT 0.1a, 253,319 0.1a, 253 0.1a, 253
Stability conditions
Compound 208C 48C RT 208C 48C RT 208C 48C RT
Conc. (mg/g)
Physical
stabilityinitial
10 H H H H H H H H H
50 H H H Xb Xb Xb H H H
60 Insoluble
Physical stability24 h
60 Insoluble
Physical stability1 month
10 H H H Observations are discontinued H H H
after 24 h as the fill formulation
is expected to be exposed to this
high level of water only during
the first 24 h
20 H H H H H H
30 H H H Xb Xb Xb
40 H H H Xb Xb Xb
50 H H H Xb Xb Xb
60 Insoluble
(X) Precipitation (crashing out) of the compound; (H) no precipitation, but rejected due to precipitation of the compound within 24 h at a
water level approximated during the primary drying process; (H) physically stable fill formulation for further chemical stability evaluation
and subsequent encapsulation.
a
Typical water content initially present in the vehicle; no water addition is required.
b
May not be applicable to MCT/LCT based fill formulations as water is unlikely to migrate into these hydrophobic vehicles.
capsules between high humidity and low humidity chemical stability evaluation. It is important to keep
conditions. A similar cycling procedure has been used in mind that the selected gel swatches and air-fills for
by Raikes et al.,140 though, to study the moisture stability evaluation have compositions commonly
uptake by softgels under various relative humidity used at various softgel manufacturers, as it would
conditions. Secondly, the migration of water from the offer the flexibility of manufacturing the final softgel
shell into the fill may be of an advantage when product at more than a single manufacturer.
encapsulating fills formulated using the enhanced When a compound is soluble and has demonstrated
solubility system (ESS) techniques (discussed in stability in a softgel compatible vehicle, it can be
Solubility Enhancers for Hydrophilic Vehicles Sec- encapsulated into softgels as a solution with minimal
tion), where a portion of the compound is present in formulation effort. On the other hand, compounds
its water soluble salt form. The chemical stability of that do not have sufficient solubility in softgel
the selected fill formulations is evaluated at 408C or compatible vehicles may require encapsulation as
higher in the presence of added water and gel suspensions. The dispersed material in a suspension
swatches that represent various potential gelatin should have a particle size of 180 mm or finer (pass
shell formulations used for encapsulation. Alter- through a #80 mesh) to achieve an acceptable blend
nately, the selected fill formulations, with no added uniformity during encapsulation and content uni-
water, may also be filled into air-fills and exposed to formity in the final softgel product.33 When a vehicle
elevated temperatures and relative humidities for for a suspension fill formulation has any solubility for
the compound, the dispersed material may undergo Abbott Laboratories) is a classic example of how
Oswald ripening and/or secondary nucleation,12 polymorphic transformation of a soluble polymorph
resulting in changes in the particle size distributions (I) to a less soluble form (II) could affect the quality of
and/or in the polymorphic nature during the shelf-life a softgel product.152,153
of a softgel product. This aspect of stability a
suspension fill formulation is typically investigated
SHELL FORMULATIONS
by subjecting the formulation with the added water
(shown in Tab. 3) to the stress testing of cycling
A softgel shell formulation typically consists of a film-
between 40 and 48C, in addition to other tests
forming material, such as gelatin, water dispersible
described above for a solution fill formulation. The
or soluble plasticizer(s), and water. The formulation
samples are observed at the end of each cycle (e.g.,
may also contain other minor additives, such as
48 h at 408C, followed by another 48 h at 48C may be
opacifiers, colorants, flavors, sweeteners, and pre-
considered as one cycle) for any changes in the
servatives. Softgels may also be coated with a variety
particle size, morphology, and polymorphism. Tem-
of polymers for certain targeted enteral delivery
perature cycling may accelerate the dissolution of the
applications.154
suspended compound in the formulation vehicle at
the higher temperature and re-crystallization upon
Gelatin
cooling, thus provide valuable information on the
physical stability of a softgel product during its shelf- The Unites States Pharmacopeia/National Formulary
life. However, the transformation may occur rapidly (USP/NF) defines gelatin as a product obtained by the
or slowly and may be reversible (enantiotropic) or partial hydrolysis of collagen derived from the skin,
irreversible (monotropic).12 white connective tissue, and bones of animals. Gelatin
A suspension fill formulation may also require a can be derived from many different sources of collagen
suspending (thickening/viscosifying) agent to prevent with cattle bones, hides, pigskins, and fish being the
settling of the dispersed material and to maintain principle commercial sources. It contains a mixture of
homogeneity throughout the encapsulation process.33 water soluble proteins (8490%), mineral salts (12%),
The widely used suspending agents for oil based and water (815%). The protein fraction contains
formulations include beeswax,141 hydrogenated vege- almost entirely of amino acids linked by amide bonds
table oils,142 and glycerol esters of fatty acids with low forming a linear polymer with a molecular weight
HLB values (e.g., Gelucire1 33/01, Gelucire1 39/01, ranging from 15000 to 250000 Da.155158 The water
Gelucire1 43/01, Compritol1 888, from Gattefossee content in gelatin usually originates from its manu-
Corporation).143,144 These suspending agents, due to facturing process.34,159
their hydrophobic and high viscous nature, could also Gelatin is derived from collagen by thermal
minimize the migration of water from the shell into denaturing with the aid of either a dilute acid (type
the fill and the diffusion of water soluble compounds A gelatin) or a dilute alkali (type B gelatin). Gelatin is
from the fill into the shell and thereby improve the usually characterized by the mode of its production
physical stability of a softgel product. The suspending and how it is produced has marked influence on its
agents used for polyethylene glycol based formula- properties. Gelatin is amphoteric in nature with its
tions include higher molecular weight polyethylene isoelectric points (IEP) ranging from 7.0 to 9.0 for type
glycols (e.g., PEG 1500, PEG 4000, PEG 6000),66 A gelatin and from 4.7 to 5.3 for type B gelatin,
cellulose polymers,73,74 colloidal silicon dioxide, poly- respectively.158 The alkaline hydrolysis causes a
vinylpyrrolidone, calcium acetate,75 and mixtures of greater degree of deamidation of the asparagine
mono-, di-, and triglycerides/mono- and di-fatty acid and glutamine amino acids in collagen, resulting in
esters of polyethylene glycols (e.g., Gelucire1 44/14, the production of a larger number of free carboxylic
Gelucire1 50/13, from Gattefossee Corporation). acid groups in gelatin than that from acid hydrolysis.
Polymorphism is a common phenomenon among The greater degree of deamidation and the resulting
many pharmaceutical active ingredients and excipi- larger number of free carboxylic acid groups from the
ents.145147 Substantial differences can exist in the alkaline hydrolytic process accounts for the relatively
rate of dissolution and bioavailability of the various lower isoelectric point of type B gelatin compared to
polymorphic forms of a compound.146,148151 These that of type A gelatin.160 Type A gelatin usually
effects of polymorphism are more critical especially in displays relatively higher plasticity and elasticity
the case of compounds belonging to BCS class II and than type B gelatin, whereas type B gelatin displays
class IV. It is critical to start the fill formulation relatively higher gel strength.
development with a stable polymorph to prevent any Commercially available gelatin is odorless, taste-
potential precipitation of the dissolved compound due less, and free-flowing granular material with a light-
to conversion of an unstable or a metastable form into amber to light-yellowish tint.158 The most favorable
the stable form. Ritonavir softgel product (Norvir1, aspect of gelatin for its use in softgels is its ability to
4126 GULLAPALLI
form thermoreversible gel in water, that is, ability to

dissolve in hot water and form a gel upon cooling, a
must have quality for sealing the softgels during
encapsulation. Gelatin is soluble in glycerin, propy-
lene glycol, dilute acids, and dilute alkalis, but
precipitates in strong acids and alkalis. The rate of
dissolution of type B gelatin is usually higher than
that of type A gelatin at a given pH of the aqueous
medium.161 The dissolution of gelatin, irrespective of
its type, was shown to be not influenced significantly
by pH at pH values above 3, but was shown to increase
and reach a plateau at pH values below 3. The higher
dissolution of gelatin at lower pH may be attributed to
the protonation of amino groups present in the
gelatin. However, the dissolution of gelatin at
lower pH was shown to decrease in the presence of
added salts, such as sodium chloride and potassium
chloride.161 Gelatin is insoluble in most organic Figure 5. Influence of pH and Temperature on the First Order
solvents, such as alcohols, acetone, and chloroform.156 Rate Constant (h1) for Decay of Gel Strength of Limed Ossein
It is important to keep these solubility characteristics Gelatin with Bloom Strength 250 g and Isoelectric pH 4.75 (Data
adopted from Croome94).
of gelatin in mind during the development of
dissolution methods for softgel products.
Gelatin undergoes hydrolytic degradation (depoly-
merization) in the aqueous gels, the rate and extent of gelatins (type B) are more susceptible to acid
which depend on the pH, temperature, and time, the degradation.162 From the studies on the hydrolytic
reaction is allowed to proceed.34,94,162,163 The depo- degradation of gelatin, Courts163 suggested that the
lymerization reactions in gelatin may be further peptide bonds involving the amino groups of serine
accelerated by the lowering of its molecular weight.34 and threonine were labile to both acidic and basic
The hydrolytic degradation of gelatin results in the hydrolysis, whereas aspartic acid peptides were
reduction of the viscosity and gel-forming ability of a susceptible to acid hydrolysis only. The glutamic acid
gelatin solution, and in the formation of weak seams peptide bonds were reported to be stable, while
during softgel encapsulation. Though gel strength glycine peptide bonds were of intermediate in
and viscosity are the two parameters commonly used stability.
to measure the extent of gelatin hydrolytic degrada- Gelatin is considered as an inactive ingredient by
tion, the gel strength has been known to be more the Food and Drug Administration (FDA). Softgel
sensitive indicator of the degradation reaction.94,162 manufacturers quality control testing for gelatin,
The degradation of gelatin (expressed as loss of gel among other things, includes bloom strength, viscos-
strength as a function of time) was shown to follow ity, iron content, and microbial testing.33,50 Bloom
first order reaction kinetics, with the reaction rates strength, also known as jelly strength, is expressed as
varying according to the pH and temperature. In the weight in grams that, when applied with a
addition, the rate constants were shown to be 12.7 mm diameter plastic plunger, will produce a
minimum between pH values 4 and 7, with the rate depression exactly 4 mm deep in a jelly containing
accelerating on either side of this pH region, as shown 6.67% w/w of gelatin in water matured for 1618 h at
in Figure 5.94 The minimum hydrolytic degradation of 108C. Bloom strength of gelatin used in a softgel shell
gelatin within the pH range of 47 was further may vary from 150 to 250 g, with the higher the bloom
corroborated by the data obtained from Courts strength, the more physically stable is the resulting
investigations,163 where minimum loss of average softgel shell. As the cost of a softgel product is related
molecular weight of gelatin was observed within directly to the bloom strength of gelatin used, gelatin
this pH range. The pH of a gelatin solution remains of a higher bloom strength is usually reserved only
constant when the degradation reaction takes place when necessary to improve the physical stability of a
at the isoelectric pH of gelatin.163 In contrast, softgel product or for large size softgels which require
the pH of the solution shifts slightly towards the greater structural strength during manufacture.33
isoelectric pH when the pH of the reaction medium is Viscosity determination is performed on a 6.67% w/w
other than its isoelectric pH and the shift becomes concentration of gelatin in water at 608C and usually
larger at high pH values.162,163 Acid treated gelatins ranges between 25 and 45 millipoise. Iron levels
(type A) are more susceptible to alkaline degradation present in the gelatin raw material is derived mainly
than to acid degradation, whereas alkaline treated from the water used in its production and should not
exceed 15 ppm as higher levels may potentially formulation at the time of encapsulation.39,4042,176
result in the color reactions with other softgel The addition of increasing amounts of a plasticizer
components. Gelatin is an excellent growth medium alters the physical properties of a gelatin film
for many bacteria and thus requires considerable resulting in an increase in its flexibility, elongation
care during its manufacture and handling to avoid at break, water retention, water vapor permeability,
contamination. oxygen permeability, and volatile solute permeabil-
ity, and a decrease in its Tg, tensile strength, and
Plasticizers
elastic modulus.43,56,57,60,155,174,175,177
The high glass transition temperature of anhydrous Among the various plasticizers studied, glycerin
gelatin (Tg > 1008C)45,164169 prevents it from forming was reported to be the most effective and practical
a flexible and acceptable film readily during the plasticizer, irrespective of type of gelatin used in a
manufacturing of gelatin capsules. Water is an shell formulation.171,175 The higher plasticizing
effective plasticizer for gelatin and reduces the Tg efficacy of glycerin was attributed to its lower
of gelatin proportionally to its water con- molecular weight178 and higher hygroscopicity175
tent.45,165,167,169,170 Coppola et al.,169 for example, than other higher polyols. When compared among
reported a decrease in the Tg of gelatin from 1608C to various nonvolatile plasticizers, the number of moles
208C when the water content in gelatin was of a plasticizer in a given amount would be higher in
increased from 2 to 28% w/w. However, due to its glycerin, and thus their effect on reducing the number
volatile nature, water will be lost during the drying of interactions between the protein polymeric chains
process resulting in a brittle and fragile shell. Thus, would be more intense.175,179 It also has been
nonvolatile plasticizers are included in the production theorized that a plasticizer with a lower glass
of gelatin ribbons for softgels. The nonvolatile transition temperature (Tg) would have a more
plasticizers are hypothesized to substitute for water pronounced plasticizing effect. In this way, the
in the vicinity of the protein chains and reduce the effectiveness of glycerin might also be explained by
proteinprotein interactions with a consequent its lower Tg (938C) as compared to sorbitol
increase in the mobility of protein chains and a (38C).175,180 Propylene glycol is more effective as a
decrease in the Tg of gelatin.169,171173 In addition, a gelatin plasticizer compared to glycerin.171 However,
plasticizer, due to its hygroscopic nature, may due to its higher solvent power for gelatin, propy-
promote absorption of moisture by gelatin that also lene glycol affects the formation of the gel structure
contributes to the reduction of the forces between the adversely, that is, it acts as more of a gel structure
adjacent polymer chains.155,174 Vanin et al.,174 in beaker. In addition, due to its higher volatility
effect, considered the reduction in the Tg of the gelatin compared with glycerin, the use of propylene glycol
films as a consequence of the total number of moles of results in the considerable deterioration in the
all plasticizers (i.e., nonaqueous plasticizers and mechanical strength of the shell material with
water) present in the films. Thus, the extent to which time.171 Furthermore, gelatin sheaths containing
a plasticizer could impart flexibility to a gelatin film is propylene glycol as the plasticizer are substantially
determined by its hygroscopicity and its ability to tackier than those containing glycerin or sorbitol as
interact with protein chains and reduce the protein the plasticizer and require much lower cooling drum
protein interactions within gelatin.155,174,175 The temperatures to extract the sheaths from the drums
reduction in the proteinprotein interactions results during softgel manufacture.37 The ability of a
in improved flexibility and handling of the shell polyethylene glycol (PEG) to act as a plasticizer is
material during its manufacturing and shelf-life. determined by its hydrogen bonding potential with
Typical plasticizers used in the softgel shell the protein chains in gelatin that in turn is influenced
formulations include glycerin, sorbitol, partially by factors, such as the number of hydroxyl groups per
dehydrated sorbitol (a blend of D-sorbitol, 1,4-sorbi- mole, molecular size, solubility, and polarity of the
tan, mannitol, and water; e.g., Sorbitol Special1, from PEG. PEG of a lower molecular weight has a larger
SPI Pharma; Anidrisorb1 or Polysorb1, from number of hydroxyl groups per mole and a higher
Roquette), maltitol (hydrogenated corn syrup; e.g., hygroscopicity compared to those of a higher mole-
Lycasin1, Roquette), mannitol, propylene glycol, low cular weight PEG and thus exhibits a more pro-
molecular weight polyethylene glycols, or a blend nounced plasticizing effect than that by the latter.
thereof. Selection of a plasticizer type and its Gelatin films plasticized with polyethylene glycols
concentration (expressed as the plasticizer-to-gelatin have also shown to exhibit a tendency for the
ratio, P/G) in a shell formulation is determined by plasticizer to migrate to the surface of the films, a
gelatin type, composition of fill formulation,60,161 and phenomenon referred to as blooming or blushing.57
compatibility with the ingredients present in a fill This phenomenon is thought to take place when the
formulation.98,100 Plasticizers are used typically at plasticizer concentration exceeds its compatibility
about 1530% w/w of the total wet mass of a shell limit in the polymer, thus causing phase separation
4128 GULLAPALLI
and physical exclusion of the plasticizer from the humidity to which the film is subjected to.43 During
polymer.181 concurrent studies, the moisture content of the film
Glycerin, due to its extreme hygroscopic nature, has also been shown to increase with an increase in
can influence gelatin to pick up substantial amount of glycerin concentration in the film and with an
moisture quickly,169 leading to a soft, tacky, and increase in relative humidity to which the film is
bloated softgel sheath that will ultimately break subjected to. Based on these observations, Hom
down or result in softgels sticking together with time. et al.43 theorized that the plasticizers and environ-
Sorbitol, on the other hand, may prone to crystal- mental relative humidity conditions control the
lization from the films that are stored at low to equilibrium water content of a gelatin film, and this
intermediate relative humidity conditions due to the equilibrium water content has the greatest effect on
insufficient availability of water to keep the plasti- the oxygen permeability through the film. In a
cizer in solution (i.e., blooming or blushing).179,182 comparative study, the oxygen permeability coeffi-
The crystallization of sorbitol would decrease the cients of gelatin films containing glycerin/sorbitol
amount of plasticizing sorbitol that in turn is (1:1) blend, hexaglycerol, and decaglycerol were
expected to increase the molecular interactions reported to be about 38.7%, 20.8%, and 19.5%,
within the gelatin network and to change the respectively, of that of a gelatin film containing
mechanical properties of the films.179 Mannitol has glycerin, at 43% plasticizer concentration, 72%
also been reported to exhibit a similar tendency to relative humidity, and room temperature.43 Thus,
crystallize from gelatin films.57 It is sometimes the use of a nonglycerin plasticizer or a blend of
advantageous to blend sorbitol with glycerin that glycerin and a higher polyol is recommended when
would yield a better control of the overall moisture encapsulating oxygen sensitive compounds in the
content of the softgel sheath. Partially dehydrated softgels.
sorbitol (a blend of D-sorbitol, 1,4-sorbitan, mannitol, Volatile fill components, such as ethyl alcohol, can
and water), in comparison, tends to pick up less readily diffuse through conventional softgel shells
moisture than glycerin and also not to prone to and usually disappear by the end of the drying
crystallization as regular sorbitol. The effectiveness processes during the softgel manufacture.60,183 Mor-
of partially dehydrated sorbitol as a plasticizer is eton and Armstrong60,183 have studied the influence
attributed primarily to its 1,4-sorbtan content and of plasticizer type and relative humidity conditions on
the interactions of 1,4-sorbitan with the gelatin the film moisture content and diffusion of ethyl
matrix.172 alcohol through the gelatin films in details. A brief
Gelatin films produced with glycerin as a plastici- summary of the results reported by these researchers
zer are less resistant to moisture and more permeable is presented in Table 4. The diffusion of ethyl alcohol
to oxygen and volatile ingredients than those through the gelatin films plasticized with glycerin
produced with a higher polyol plasticizer, such as was shown to accelerate with an increase in the film
xylitol, sorbitol, maltitol, or a blend of glycerin with a moisture content. A similar trend, though at a
higher polyol.43,60,175,183 The oxygen permeability significantly much lower rate, was also seen in
through a gelatin film has been shown to increase gelatin films plasticized with xylitol. It appears from
exponentially with an increase in glycerin concentra- Table 4 that the relative humidity conditions control
tion in the film and with an increase in relative the equilibrium water concentration in a gelatin film,
Table 4. Influence of Plasticizer Type and RH on Moisture Content and Diffusion of Ethyl Alcohol through Films Made from
150 Bloom Lime Bone Gelatin60,183
Moisture
Plasticizer Type Exposure Content % Apparent Diffusion
and Concentrationa to % RHb w/w Range Coefficient mm2 min1 Range
Glycerin, 20% w/w 11 4.566.44 3.453.81 105

33 7.439.32 4.605.24 105
54 13.2019.80 8.6146.2 105
75 30.7034.10 51.768.1 105
Sorbitol, 20% w/w 33 8.588.82 No diffusion detected
Xylitol, 20% w/w 33 8.008.14 No diffusion detected
54 13.1014.39 0.7591.68 105
75 26.5033.67 5.6722.1 105
Lycasin, 20% w/w 75 17.0023.10 1.161.47 105
a
Based on total wet mass.
b
Exposed to the selected relative humidity (RH) at ambient temperature (21.523.78C).
and this equilibrium water concentration appears to observable interactions with gelatin and other
have the greatest effect on the diffusion of a volatile ingredients used in the softgels.187 Due to its high
fill component through the film, that is, for a given refractive index (2.552.76), titanium dioxide has
plasticizer type, the higher the moisture content of a excellent light-scattering properties and the extent of
gelatin film, the more rapid the diffusion of a volatile light-scattering by titanium dioxide can be altered by
component through it. However, the diffusion process varying its particle size186,188,189 and concentration
was significantly lower through the gelatin films used in a shell formulation.190 As Rayleighs theory
containing a higher polyol plasticizer, such as xylitol, implies, the shorter wavelengths of light are more
sorbitol, or lycasin, compared to that through the efficiently scattered by smaller particles, that is,
films containing glycerin as the plasticizer, at similar the finer the particle size of the opacifier the more
film moisture contents. Thus, the loss of a volatile fill effective it is in scattering the UV light below 400 nm.
component due to diffusion can be minimized by the However, as the particle size of the opacifier reaches
use of a higher polyol plasticizer, maintaining low below 50 nm, its scattering power decreases in the
shell moisture content, and protecting the softgel visible range making the film more transparent than
product against high humidity conditions. one with a larger particle size.188,189
Titanium dioxide is highly hydrophobic and gen-
erally occurs as aggregated particles that should be
Colorants and Opacifiers
dispersed and wetted thoroughly before its addition to
Coloring agents are included in a softgel shell the molten gel mass.191 The effectiveness of a shell
formulation to provide elegance to a softgel product material to provide light protection to an encapsu-
and also to provide a distinctive appearance that may lated compound is critically dependent on how well
serve to differentiate a particular softgel product from the opacifier is dispersed in the gel mass. Ideally, for
others that have a similar physical appearance. The an opacifier to be more effective against UV light
coloring agents can be dyes (water-soluble sub- transmittance, it should be dispersed as individual
stances), lakes (insoluble forms of a dye that result crystals or small agglomerates of two or three
from its irreversible adsorption onto a hydrous metal crystals. Aggregates of many finer crystals behave
oxide), inorganic pigments (substances such as as though they are one large particle, thus scattering
titanium dioxide or iron oxides), or natural colorants visible light and exhibiting poor effectiveness in the
(colored compounds not considered dyes per se, such UV range.188
as riboflavin).184 The most important properties of a The light transmission through a gelatin film
coloring agent are its depth of color and resistance to can also be reduced substantially either with the
fading over time. Coloring agents can be graded on increase of its thickness at a given opacifier
their efficiency in reflecting desired colors of visible concentration or with the increase of the opacifier
light as well as on their molar absorptivities at concentration in the film.190 The light transmission
characteristic wavelengths of absorbance.184 Coloring through a gelatin film was shown to be diminished
agents are subject to federal regulations and conse- with the increase of titanium dioxide concentration
quently the current regulatory status of a given up to 1% in the film and plateauing afterwards.190
substance must be determined before it is used. It is The addition of an opacifier to a shell formulation
desirable that the coloring agents should be physi- may also potentially increase the tortuosity of the
cally and chemically nonreactive with other ingre- path that the permeating oxygen and light must flow
dients present in the softgel product. Anionic dyes are through to reach the fill.43 However, the effect of an
known to interact to a greater extent with a cationic opacifier on the permeability of oxygen through
type A gelatin than with an anionic type B gelatin.185 gelatin films was shown to be observable only
These interactions could potentially effect the disin- at opacifier concentrations substantially higher
tegration of the gelatin shell. than what is commonly used in a capsule shell
An opacifier is included in a shell formulation to formulation.
provide light resistance when photosensitive com-
pounds are encapsulated into softgels. An opacifier
DISSOLUTION
may also be included in a shell formulation when
encapsulating an unaesthetic fill formulation, such as
Dissolution of Softgel Shell
a disperse system that is prone to phase separation or
sedimentation. Titanium dioxide is the most com- The availability of a compound formulated in a softgel
monly used opacifier and is typically used at about for absorption depends on the initial dissolution and
0.51.0% w/w of a shell formulation to impart rupture of the softgel shell and subsequent release
sufficient opacity to the shell. Titanium dioxide is a and dissolution of its fill contents in the GIT fluids.
white, odorless, tasteless, inert, nonhygroscopic Thus, these two processes need to be monitored
powder186 that has been shown to undergo no during the release and shelf-life of a softgel product.
4130 GULLAPALLI
Problems in the dissolution and rupture of the softgel chemical reactions occurring within the gelatin are
shell may become apparent upon aging, when exposed distinctly different.204,205 Physically, exposure of
to physical conditions, such as heat,192,193 high gelatin shell to either elevated temperatures or
temperature and humidity, UV radiation, g-radia- aldehydes results in a decrease of its disintegra-
tion,194 and rapid drying,47 and when exposed to tion, dissolution, and swelling properties, and an
chemical substances, such as aldehydes, ketones, increase of its gel strength, a clear indication of the
imines, and carbodiimides.195,196202 These problems formation of three dimensional networks within
are attributed to cross-linking of gelatin (pellicle the gelatin.
formation) that causes the gelatin shell to become Chemically, aldehydes are known to form methy-
swollen, tough, rubbery, and insoluble in water. lene bonds between two amino groups on adjacent
Cross-linking of gelatin gives rise to the formation of a gelatin chains or within the same chain, as
very thin film during the dissolution testing of a illustrated in Figure 6. The aldehyde induced
softgel product. The film is mechanically weak and cross-linking of gelatin is thought to involve the e-
can easily be punctured. However, the film does not amino functional groups present in the lysine
disrupt easily with gentle agitation under normal moieties and the guanidino functional groups pre-
dissolution conditions.203 sent in the arginine moieties of the gelatin
chain.196,197,206211 Both of these amino acids, lysine
and arginine, have long, reactive side chains that
Mechanism of Gelatin Cross-Linking
can extend farther out from the polypeptide chain
The ultimate effects of exposure to elevated than other groups and thus can participate more
temperatures on the physical properties of the easily in the inter and intra molecular reactions.207
gelatin shell are known to be similar to those of In addition, hydrogen bonding is proposed to provide
exposure to aldehydes, though the mechanisms of the added stability to the lysine-arginine cross-link
Figure 6. Possible mechanism of formation of methylols of lysine and arginine and subsequent
cross-links formation in gelatin (adopted from Taylor et al.,207 Albert et al.,209 Gold et al.210).
and arginine-arginine cross-link (Fig. 6). Evidence The aldehyde and other carbonyl impurities in
obtained from 13C nuclear magnetic resonance softgels may originate from the autooxidation of
(NMR) studies using 13C labeled formaldehyde as materials containing polyoxyethylene moieties in
a cross-linking agent strongly suggests the forma- their structures (e.g., polyethylene glycols, methox-
tion of methylols (i.e., hydroxylmethyl) of lysine ypolyethylene glycols, polyoxyethylene fatty acid
residues initially and of arginine residues later, esters, polyoxyethylene sorbitan fatty acid esters,
which react together resulting in the formation of polyoxyl 40 hydrogenated castor oil).95,213218 Rayon
lysine-to-arginine and arginine-to-arginine cross- coiler, included in the package presentations, is
links in gelatin, but no evidence has been found in known to be another source that produces furfural
the formation of lysine-to-lysine cross-links in (2-furaldehyde) at the accelerated stability conditions
gelatin exposed to aldehydes.207209 As the formation that could potentially cross-link gelatin.219,220 On the
of arginine methylols was identified to coincide with other hand, drug molecules containing carbonyl
the initiation of gelatin cross-linking reactions, its functional groups in their structures (e.g., nimesu-
formation was hypothesized to be the rate limiting lide, rofecoxib, macrolide antibiotics) may also induce
step in the cross-linking of gelatin. The rate of cross- the cross-linking of gelatin and thereby reduce the
linking in gelatin by aldehydes was shown to be dissolution of the shell material.221,222
strongly influenced by humidity with maximum
cross-linking occurring around 6070% humidity.209
Minimizing Gelatin Cross-Linking
Due to the high pKa value of the e-amino functional
group (pKa 10.79) in lysine and of the guanidino The cross-linking of gelatin in a softgel shell can be
functional group (pKa 12.48) in arginine, both reduced by using excipients with low aldehyde
these functional groups exist in their protonated content in the fill formulation, by using excipients
forms at acidic pH and thus are not expected to be containing abundant free amino groups (e.g., glycine,
available to react with aldehydes.210 In contrast, lysine) in the shell formulation that can compete with
since both of these functional groups exist primarily the amino groups present in the gelatin chain for the
in their unprotonated forms at alkaline pH, they can available aldehydes originating from the components
potentially react with aldehydes, resulting in cross- used in the softgel (i.e., aldehyde scavengers), and/or
linking. Gold et al.210 suggested that fill formula- by masking the amount of amino groups available
tions, containing excipients suspected to be con- along the molecular chain of the gelatin through
taminated with aldehydes, should be formulated at covalent bonds with suitable masking agents.223
the lowest possible pH to prevent gelatin cross- Succinic acid is an agent often used to mask the
linking. amino groups present in the gelatin chain through
In contrast to the cross-linking mechanism in the covalent bonds (succinization). The dicarboxylic acid
presence of chemical agents, elevated temperat- nature enables succinic acid to both the reaction of
ures are known to promote condensation reactions one carboxylic group with an accessible amino group
between a carboxylic group on a gelatin chain and in the molecular chain of the gelatin while the second
an amino group on an adjacent gelatin chain (or carboxylic group concurrently provides steric preven-
within the same chain), as illustrated in Eq. (1).192193 tion of access of the cross-linking agent. However, a
Eq. (1) shows the effect of elevated temperatures on disadvantage of the succination approach is the
gelatin gelatin shell prepared using the succinated gelatin
is usually highly permeable to volatile solvents (e.g.,
Chain 1 COOH H2 N Chain 2 ! Chain 1 ethyl alcohol) and migratable ingredients (e.g.,
propylene glycol).
CO NH Chain 2 H2 O (1) Incorporation of both an amino acid (e.g., glycine)
and a carboxylic acid (e.g., citric acid) into the powder-
Whether it is aldehyde induced or heat induced, fill of hydrochlorothiazide hard gelatin capsule was
cross-linking of gelatin results in the formation of shown to provide a reduction in the cross-linking of
three dimensional molecular networks of a higher gelatin.224,225 The carboxylic acid was believed to
molecular weight with the loss of ionizable groups provide an acidic environment necessary to minimize
(i.e., R-NH2 and R-COOH) than the original mole- the hydrolytic degradation of hydrochlorothiazide
cules, leading to the reduced solubility of gelatin. into its carbonyl impurity, whereas the amino acid
Alternately, the loss of ionizable groups in gelatin and was believed to function by acting as the carbonyl
the resulting decrease in its solubility may also scavenger. However, this approach is fraught with
arise from the ionic, hydrogen, and van der Waals the disadvantage of limited solubility of the stabiliza-
interactions of these groups with other compounds tion excipients in the nonaqueous vehicles commonly
used concurrently in the shell formulation, such as used in softgels.226 To circumvent these solubility
FD&C red #3 and FD&C red #40 dyes.185,212 issues, the WIPO patent application WO 03/103582176
4132 GULLAPALLI
proposes the use of an amino acid moiety (e.g., enzymes in the small intestine as compared to the
glycine, lysine) in the shell and a softgel compatible gastric enzymes like pepsin. It may be the cause for
ester of carboxylic acid (e.g., tocopherol acetate, the delayed capsule rupture in vivo.
tocopherol succinate, D-alpha tocopheryl polyethylene
glycol succinate-TPGS) in the shell, fill, and/or
Dissolution of Softgel Fill
lubricant to reduce the cross-linking of gelatin. The
extent of gelatin cross-linking in the softgel shell may Changes in the dissolution of a fill material are
also be influenced by the type of functional group(s) usually apparent (a) when there is a change in
present in the structures of the compounds encapsu- particle size distributions (e.g., due to Oswald
lated. Compounds containing either a primary amine ripening) and/or polymorphic nature (e.g., due to
group(s) (e.g., isoniazid, acyclovir) or a secondary secondary nucleation) of the suspended material in a
amine group(s) (e.g., ethambutol) may interact with suspension fill formulation,12 (b) when there is
the aldehyde impurities present in the fill formula- crystallization of a solubilized compound from a
tion, that is, act as aldehyde scavengers, and thereby solution fill formulation,153 or (c) when a poorly
prevent the cross-linking of gelatin.222 soluble compound is dissolved in hydrophilic solvents
and cosolvents (e.g., type IV formulations under
Poutons LFCS109). In the latter case, upon dilution
Dissolution Testing: Influence of Digestive Enzymes on
with the GIT fluids in vivo or with the dissolution
Gelatin Cross-Linking
medium in vitro, the hydrophilic fill vehicle may
The USP Chapters <711> and <2040> on Dissolu- dissolve or disperse in the aqueous fluids and thereby
tion227 provide guidance and procedures for dissolu- expose the solubilized water-insoluble compound to
tion testing for dosage forms administered orally. For aqueous fluids, leading to erratic and inconsistent
gelatin capsules that failed tier 1 dissolution testing precipitating of the compound (crashing out).70
(i.e., in a medium with no enzymes) due to gelatin Surfactants are commonly used in the dissolution
cross-linking, the USP recommends the use of medium during the dissolution testing of poorly
digestive enzymes (i.e., pepsin or pancreatin) in the soluble compounds and oily formula-
dissolution medium during tier two dissolution tions.1,144,229,232236 The use of surfactants in the
testing. These enzymes digest the cross-linked gelatin dissolution medium for the dissolution testing of
and thereby promote the dissolution and rupture of poorly soluble compounds has been proposed to be
the cross-linked gelatin shell. The use of these physiologically meaningful as these surfactants
digestive enzymes in the dissolution medium is mimic those natural surfactants, such as bile acids,
justified on the grounds that such enzymes are also bile salts, and lecithin present in the GIT.232,233
present in the GIT.228,229 Additionally, Buri and Hainbert-Droz237 suggested
Softgels that failed the tier 1 dissolution testing but that the natural surfactants could be interchanged
passed the tier 2 dissolution testing (Fail/Pass) were with a synthetic surfactant, such as sodium lauryl
shown to be bioequivalent to those which passed the sulfate, for solubilizing poorly soluble compounds.
tier 1 dissolution testing, whereas softgels that failed The selection of a type and concentration of a
both tiers of dissolution testing (Fail/Fail) were shown surfactant and other solutes used in the medium for
to be bioinequivalent to those passed either one or dissolution testing is based on a variety of factors,
both tiers of dissolution testing.230 Severe cross- such as (a) aqueous solubility, ionic nature (pKa; pH-
linking of gelatin (Fail/Fail) was thought to result in solubility profile), and dose of the compound; (b)
the decreased availability of its peptide bonds compatibility of the surfactant with the compound;
towards the proteolytic enzymes (i.e., pepsin and (c) compatibility of the surfactant with the gelatin
pancreatin), leading to decreased rate and extent of shell;238241 (d) critical micellar concentration
proteolysis of gelatin by these enzymes. The proteo- (CMC) of the surfactant; and (e) degree of partition-
lytic enzymes may also cease to recognize the carboxyl ing of the compound into the surfactant micelles
ends of the aldehyde-derivatized lysine and argi- (i.e., micellar loading).234 Some commonly used
nine.231 In some cases, though the severe cross- surfactants in the dissolution medium include
linking may not adversely affect the bioavailability sodium lauryl sulfate (SLS), polyoxyethylene sorbi-
(AUC(01) and Cmax) of a compound, but it could tan monolaurate (Polysorbate 20), cetyltrimethy-
potentially delay the onset of its absorption (Tmax) due lammonium bromide (CTAB), polyoxyl castor oil
to the delayed shell rupture in vivo.231 Based on a (Cremophor EL), hexadecyltrimethylammonium
detailed gamma scintigraphy study to identify the bromide (HTAB), polyethylene glycol tert-octylphe-
time and location of disintegration of cross-linked and nyl ether (Triton), nonylphenol ethoxylate (Tergi-
noncross-linked capsules in vivo, Digenis et al.231 tol), cyclodextrins, and lecithin.234 Use of aqueous-
suggested that the aldehyde induced cross-links were organic solvent mixtures is strongly discouraged as
more susceptible to cleavage by the pancreatic the dissolution medium for softgels as these solvents
could potentially prevent dissolution of gelatin shell and concentrations of solutes in the dissolution
even when it is free from cross-linking, resulting in medium used either to adjust pH, buffer strength,
reaching misleading conclusions. In addition, the or ionic strength of the dissolution medium, or to
use of these aqueous-organic medium has no enhance the solubility of a poorly soluble compound,
relevance to the physiological environment and is could play a critical role in the dissolution of a softgel
not likely to generate meaningful data for in vivo product. It is worthwhile to evaluate all these
interpretation.229,232,233 variables during the development of dissolution
Surfactants, used to improve the dissolution of methodology for a softgel product. Examples of
poorly soluble compounds and oily formulations, are dissolution procedures used for some marketed soft-
also known for their denaturing effects on the gel products are presented in Table 2.
digestive enzymes used in the dissolution medium
for cross-linked softgel formulations.242,243 The USP
recommended levels of pepsin or pancreatin may be STABILITY
sufficient for the digestion of cross-linked softgels in
the absence of a surfactant. The cross-linked softgels Physical Stability
were shown to pass the tier two dissolution testing
Crystallization of Solubilized Compounds
only when the enzyme was introduced into the
medium initially followed by the surfactant few Due to the high initial water content of the
minutes afterward. These softgels failed to meet shell formulation at the time of encapsulation
the dissolution specification when enzyme and ( 30%),39,40,41 water migrates from the shell into
surfactant were introduced into the medium together the fill and vice versa during the drying and
at the onset of dissolution testing. Thus, it was subsequent equilibrium processes (Fig. 2). The
recommended to introduce the surfactant into the rate and extent of water migration is influenced
dissolution medium after the initial enzyme digestion by the composition of shell formulation (e.g., type
of cross-linked softgels had occurred.244,245 and concentration of plasticizer, presence of addi-
Sodium lauryl sulfate, an anionic surfactant, could tives),37,43 composition of fill formulation,40,41,69,72,139
bind to the cationic charges on gelatin at pH values and environmental conditions to which the softgels
equivalent to gastric pH.239,241,246248 Due to the are subjected to.43 The improved bioavailability of a
high pKa values of the amino functional groups in compound encapsulated in a solubilized form is due to
gelatin, these groups exist in their protonated form at the presentation of the compound at the site of
gastric pH and thus are expected to undergo ionic absorption as a solution. The objective of improving
interactions with the negative charges on the anionic bioavailability of a compound through solubilization
surfactant. The anionic charges of gelatin, on the may be defeated if the solubilized compound crystal-
other hand, may bind to cationic surfactants, such as lizes either within the softgel due to water migra-
cetylpyridinium chloride, dodecylammonium chlor- tion68,69 or upon coming into contact with the aqueous
ide,249 and dodecyl amine hydrochloride.246 These fluids in the GIT.70,72 Studies by Serajuddin et al.69
interactions may influence the solubility and dissolu- demonstrated gross crystallization of a poorly soluble
tion of the capsule shell.241,247 The rate of dissolution test compound in the softgels when the compound was
of a gelatin shell in acidic solutions (pH < 5), for encapsulated as a PEG 400 based solution. However,
example, was shown to decrease as the concentration no such crystallization of the compound was observed
of sodium lauryl sulfate in the dissolution medium in the softgels when the test compound was encapsu-
was increased.241 In addition, the rate of dissolution lated as a Gelucire1 44/14PEG 400 (6:1) based
slowdown caused by the surfactant was shown to be solution. The investigators attributed the absence of
more pronounced with the increased ionic strength in crystallization of the compound in the softgels
the medium. Use of a nonionic surfactant (e.g., containing Gelucire1 44/14PEG 400 (6:1) based
polysorbate 20, polysorbate 80) may be considered fill to minimal migration of water from the shell into
in place of an ionic surfactant during the dissolution the fill. Indeed, the reported water contents of the fill
testing of poorly soluble compounds to minimize the and the shell at equilibrium were 6.4 0.1% and
gelatin-surfactant interactions and ensuing slow- 9.6 0.2%, respectively for the PEG 400 based fill
down of disintegration of gelatin shells.247 versus 1.1 0% and 5.6 0.1%, respectively, for the
Equally important, the impurities present in a Gelucire1 44/14PEG 400 based fill. Propylene
surfactant and other electrolytes used in the dissolu- glycol, due to its lower viscosity and higher plasticiz-
tion medium could influence the CMC of the ing efficacy for gelatin, requires lower water content
surfactant, and size and loading capacity of micelles in the production the gel mass compared to glycerin or
for a compound and thus influence the ultimate sorbitol as the plasticizer. The initial lower water
solubility and dissolution rate of the compound in the content of the shell formulation containing propylene
dissolution medium.234,241,250,251 Therefore, the type glycol as the plasticizer may also have the advantage
4134 GULLAPALLI
of a comparatively smaller amount of water migration shown to provide some marginal improvement in the
into the fill that could potentially minimize the elasticity to the shell containing the encapsulated
precipitation of sparingly water soluble compounds in PEG 400 fill without the added glycerin on aging. In
the fill.37 Thus, the extent of water migration within contrast, it was shown that the incorporation of or
the softgel and ultimate physical stability of a softgel migration of increasing amounts of PEG 400 into the
product can be controlled through the careful selec- shell containing glycerin or sorbitol as the plasticizer
tion of a suitable solubilizing vehicle as the fill and a reduced its elasticity and increased its brittleness.255
suitable plasticizer in the shell. It was speculated that the increased PEG 400
Water migration from the shell into a lipid fill, concentration in the shell may induce migration of
though in minute amounts compared to polyethylene glycerin from the shell into the fill when glycerin was
glycol based fills, may still have profound conse- the plasticizer and incompatibility between PEG 400
quences on the solubility of some compounds in lipid and sorbitol within the shell due to their immiscibility
vehicles.252254 The presence of water in a lipid when sorbitol was the plasticizer.
vehicle may alter the solubility of a compound by one
of three ways: (a) via disruption of hydrogen bonding Chemical Stability
between the molecules of the lipid and those of the
Reactions between Encapsulated Compounds and
solubilized compound and thereby reducing the
Excipients
solubility if this hydrogen bonding is a major driving
force for the solubilization of the compound in the Compounds containing reactive moieties in their
lipid;252 (b) via inducing reorganization of the lipid structures have known to react with hydroxyl
molecules within the matrix from the original compounds used in softgels either as solvents,
molecular arrangement existed in the absence of plasticizers, or to meet other functional requirements
water;254 and/or (c) via formation of a hydrate of the (e.g., polyethylene glycols, propylene glycol, glycerin,
dissolved compound having reduced lipid solubi- sorbitol, or their partial esters), resulting in the
lity.253 Land et al.,253 for example, have shown that formation of esters, carbonates, and amides.100,256260
the presence of even ultra-low water content in the Though these reaction products may be ultimately
lipids was sufficient to induce hydrate formation and hydrolyzed back to their parent compounds in the
reduce the lipid solubility of compounds, such as GIT, the bioavailabilities of the parent compounds
anhydrous testosterone. could be reduced significantly.259,261,262 The rate and
extent of these reactions between an encapsulated
compound (or its degradation product) and a hydroxyl
Deterioration of Mechanical Strength of Shell
component in a softgel are influenced by (a) intrinsic
Polyethylene glycols of a lower molecular weight chemical reactivity of the compound, (b) state and
(400D), used as fill vehicles, have a higher affinity extent of ionization of the compound, (c) hydroxyl
for water and glycerin used in the shell formulation, content of the solvent, (d) water content of the fill, (e)
leading to the migration of these shell components manufacturing conditions, and (f) storage conditions.
into the polyethylene glycol fill. The migration of The ionized form of a carboxylic acid compound,
water from the shell into a polyethylene glycol fill may such as ibuprofen, (R-COO) is relatively less reactive
be reduced to some extent by the use of a higher towards a hydroxyl compound compared to its
molecular weight polyethylene glycol that has a lower unionized form (R-COOH).100 In addition, as ester-
hygroscopicity, for example, substituting PEG 600 for ification and hydrolytic reactions are generally
PEG 400. Migration of a plasticizer from the shell into reversible, hydrolysis of the formed esters back to
the fill in a softgel could result in the reduced the parent compounds could be potentially achieved
elasticity (flexibility) and increased brittleness of the through increasing the amount of available water in
shell shortly after production or on storage, especially the fill formulation. Thus, the rate and extent of
when exposed to cold temperatures.40,41,255 The degradation (i.e., esterification) of a carboxylic acid
elasticity of the shell in such a case could be markedly compound in the presence of a hydroxyl compound
improved by the inclusion of a small amount of can be reduced through partial ionization of the
glycerin in the polyethylene glycol fill.255 The carboxylic acid groups (complete ionization, though
improvement in the elasticity of the softgel shell further reduces the esterification reaction, also
containing the encapsulated PEG 400 fill with the reduces the enhanced solubilization advantage
added glycerin (or propylene glycol) was attributed to gained by using a counter ion technique, as discussed
the equilibration of glycerin between the shell and the in Solubility Enhancers for Hydrophilic Vehicles
fill, resulting in the reduced migration of the Section), reduction in the amount of available
plasticizer from the shell into the fill. Substitution hydroxyl content (i.e., use of a lower amount of a
of a portion of glycerin with partially dehydrated hydroxyl solvent or use of a solvent with lower
sorbitol (Sorbitol Special) as a plasticizer was also hydroxyl content, e.g., use of PEG 600 instead of PEG
400 or MPEG instead of PEG), increase in the amount present in a polyethylene glycol or in a related
of available water in the softgel, and use of milder material are dependent upon the molecular weight
manufacturing conditions.98,100,258 and age of the polymer and the extent of its
The decomposition of aspirin in polyethylene exposure to air during its storage.214,267,270 The
glycols in the absence of water was also attributed higher the molecular weight of the polymer, the
to the transesterification reactions, resulting in the lower the concentrations of these products and
formation of salicylic acid and acetylated polyethy- the older the polymer, the greater the concentrations
lene glycols.256,257,263 These transesterification reac- of these products. The relatively higher levels of these
tions were shown to be affected by temperature (rate products observed in a polyoxyethylene polymer of a
at 608C > 458C > 278C > 48C) and the number of lower molecular weight may be related to the increase
hydroxyl reactive sites available on the polymer in the mobility of the polymer chains allowing for the
chain (rate in PEG > methoxyPEG > PEG acetate). increased autooxidation reactions.267
Compounds encapsulated in softgels could poten- The reactive products generated from the autoox-
tially undergo hydrolytic degradation during the idation of polyoxyethylene polymers have been
shelf-life of a product as a result of migration of water implicated in the degradation of several compounds
from the shell into the fill. During the softgel formulated in polyethylene glycols.95,215,218,269,271
formulation development for a poorly water soluble The carboxylic acids so formed during the autooxida-
investigational compound, VX-497, solubilized in tion reactions could lower the apparent pH of an
PEG 400, Kochling et al.260 demonstrated the aqueous polyethylene glycol solution, the extent of
hydrolysis of urea bonds in the compound even at which is dependent upon how much autooxidation of
storage temperatures as low as 58C. The hydrolytic polyethylene glycol might have taken place during its
degradation of the compound in PEG 400 vehicle was handling and storage.218 The lowered pH can degrade
attributed to the moisture content of the fill, reported compounds that are susceptible to hydrolytic degra-
to be about 7%. The investigators also demonstrated dation under acidic conditions.95 On the other hand,
how reactions between PEG 400 and the urea the reactive aldehydes can cross-link compounds
carbonyl groups present in the compound and in its containing amino groups in their structures through
structurally related process impurity could result in methylene groups.95,272274 The mechanism of these
the formation of a series of PEGylated compounds. cross-linking reactions is similar to the methylene
The PEGylation reactions of the compound and its bonding between two amino groups on adjacent
process impurity with PEG 400 were shown to be gelatin chains, as described in an earlier section.
temperature and time dependent, that is, the higher The autooxidation reactions in polyethylene glycols
the manufacturing process temperature and the and their related materials and the formation of
longer the mixing time, the greater the concentra- reactive products resulting from these reactions can
tions of these PEGylated products. In this case, the be minimized effectively by the use of an antioxidant
rate of degradation of the compound (i.e., PEGylation) in the fill formulation, purging the formulation with
was successfully reduced and the overall quality of nitrogen during its manufacturing, and thoroughly
the drug product was improved through removal of deaerating the formulation under vacuum before its
the process impurity during the manufacture of the encapsulation into softgels.215,218
drug substance, and lowering of the manufacturing In addition to polyethylene glycols and their
temperature and shortening of the mixing time related materials, peroxide and aldehyde impurities
during the manufacture of the drug product. are also known to present in other excipients
and packaging components used with the softgel
products.219,220,268,275278 The peroxide impurities in
Autooxidation of Excipients and Affects on Stability of
povidone, a typically used solubility enhancer and
Encapsulated Compounds
viscosifiers in softgels,55,56,67,98 are known to promote
Polyethylene glycols and materials containing poly- significant degradation of oxidatively sensitive com-
oxyethylene moieties in their structures are known to pounds even in solid-state (e.g., degradation of
undergo autooxidation in the presence of oxygen and raloxifene to its N-oxide in tablet formulations
produce reactive organic peroxides and hydrogen containing povidone as an excipient277). These per-
peroxide.95,213218,264268 The organic peroxides are oxides are present in povidone initially as process
further degraded to produce short chain carboxylic impurities and are known to increase in content with
acids and aldehydes. It has been postulated that time in the presence of atmospheric oxygen.279
polyoxyethylene moieties undergo oxidative decom- Formaldehyde, a known contaminant in packaging
position at high temperatures in the presence of water material, was shown to degrade ropinirole to its
to ethylene glycol, which may then be oxidized further hydroxymethyl adduct.276
to form formaldehyde.269 The amounts of these Equally important, the minor impurities present
reactive peroxides, carboxylic acids, and aldehydes in a gelatin shell, for example, ammonia resi-
4136 GULLAPALLI
due resulting from the amide hydrolysis of asparagine or loss of any critical component present in the
and glutamine residues during the acid or alkaline SEDDS and SMEDDS fill formulations could also
hydrolysis of collagen, could also potentially have a significant negative impact on the in vitro and
induce degradation of encapsulated compounds.280 in vivo performance of these formulations.37,284 On
The degradation of such encapsulated compound can the other hand, a shell material containing encapsu-
be minimized through the use of gelatin with reduced lated acid salts, mineral acids, and organic acids may
ammonia content. A thorough understanding of these be at the potential risk of acid hydrolysis of the
reactions and their effects on the stability of polypeptide chains in gelatin due to the migration
encapsulated compounds is essential in improving these compounds into the shell.143,161,281,285
the quality of a softgel product. The loss of a volatile component from a fill formula-
tion can be minimized, though not completely avoided,
Migration of Solutes between Fill and Shell Components
by packaging the softgel product in a solvent tight
Softgels, due to their very dynamic nature, could packaging material, such as an aluminumaluminum
potentially give way to considerable migration blister (Fig. 7).59 Other ways to overcome the problem is
(partitioning) of solutes between a shell and an the use of a nonvolatile cosolvent that is not susceptible
encapsulated fill.60,183,281,282 The extent of migration to any diffusion into and across the capsule
of a solute between a fill and a shell depends on the shell.37,59,286 A variety of nonvolatile cosolvents have
hydrophilicity of the solute, composition of the shell been investigated to substitute ethyl alcohol in the
formulation (e.g., type and concentration of plastici- preparation of SEDDS and SMEDDS for softgel
zer), nature of the fill vehicle, and the conditions to encapsulation, including propylene glycol, diethylene-
which the softgel product is subjected to during its glycol monoethyl ether (Transcutol1), tetrahydrofur-
manufacturing and shelf-life. Compounds with furylalcohol polyethylene glycol (Glycofurol);283,287
higher aqueous solubility can preferentially migrate propylene carbonate, mixture of propylene carbonate
from an encapsulated fill into a hydrophilic shell. In and polyoxyethylenepolyoxypropylene block co-
contrast, lipophilic compounds migrate from a fill to a polymers;59,104 dimethylisosorbide;288 and ethyl
shell to a lesser extent. Investigations by Armstrong lactate.104 SEDDS and SMEDDDS containing a
et al.281 on the migration of compounds of varying lipophilic cosolvent (e.g., triacetin, triethyl citrate,
aqueous solubilities from a fill into a shell suggested acetyltriethyl citrate) instead of a hydrophilic cosol-
that the rate and extent of migration of the vent have also been discussed in the literature.104,286
compounds followed the same rank order as their Cosolvents of a lower viscosity are usually preferred to
aqueous solubilities, but had no relationship to the those of a higher viscosity in the preparation of
solubilities of these compounds in the fill vehicle. SEDDS and SMEDDS as the use of the former may
Interestingly, most of the solute migration appeared
to take place during the tumble drying process
(primary drying process), followed by tray drying
process (secondary drying process). The larger extent
of migration of a solute during the drying processes
may be the result of either diffusion of water from the
fill into the shell and then out, carrying out the
hydrophilic solute in the process or higher water
content and lower viscosity of the shell material
before the completion of drying processes that would
favor the partitioning of the hydrophilic solute into
the shell. During the migration process, some of the
solute may further migrate to the outer surface of the
softgel shell, from which it could be eroded by friction,
or else removed by washing.281
Ethyl alcohol, a cosolvent commonly used in
SEDDS and SMEDDS, is another example of a fill
component that was also shown to diffuse readily
through the conventional softgel shells at such a rate
that most of ethyl alcohol would have disappeared
from the fill by the end of the drying processes.60,183
Loss of ethyl alcohol from an encapsulated fill could Figure 7. Loss of ethyl alcohol cosolvent from softgels contain-
ing a cyclosporin SMEDDS fill formulation (~) packaged in bottles,
potentially result in the precipitation of a dissolved stored at RT; (*) packaged in bottles, stored at 358C/75%RH; (^)
compound, especially when the cosolvent is used to packaged in aluminum foil, stored at RT; (&) packaged in alumi-
maintain the compound in solution.283 The migration num foil, stored at 358C/75%RH (adopted from Kim et al.59).
be better able to promote emulsification with minimal prone to water induced crystallization or hydro-
effort. lytic degradation.
(6) Even after an organization chooses to initiate
development and commercialization of a com-
ALTERNATE DELIVERY STRATEGIES FOR pound as a softgel product with improved bioa-
NONAQUEOUS FORMULATIONS vailability as the first-line introductory dosage
form, the relatively higher production costs
Softgel delivery system offers the advantage of compared to those of some other dosage forms,
conveniently delivering a nonaqueous liquid or formulation/excipient related issues, and/or
semi-solid matrix containing a dissolved or dispersed some other aforementioned issues would encou-
compound as a unit dose solid dosage form. However, rage the organization to pursue an alternate
a variety of factors may influence the decision making dosage form at a later stage. Some examples of
process of an organization in the development and such fruitions include reformulation of Agener-
introduction of a compound into commercialization as ase1 softgel into Lexiva1 tablet containing a
a softgel product. These factors may be strategic or prodrug of the compound (GlaxoSmithKline),
technical and worth further discussion: reformulation of Fortovase1 softgel into
Invirase1 tablet and capsule containing the
(1) Manufacture of softgels is inherently a very mesylate salt of the compound (Roche Pharma-
complex, labor-intensive, and time consuming ceuticals), and reformulation of Kaletra1
process that requires not only acquiring and softgel into tablet with increased drug loading,
maintaining specialized and costly equipment, improved stability, lowered restrictions on sto-
such as gel reactors, encapsulation machines, rage conditions, and reduced food effects
dyes, tumble dryers, and drying tunnels but (Abbott Laboratories). On the other hand, some
also in-house technical and operational exper- compounds that were originally introduced into
tise and sourcing high quality gelatin. As a commercialization as a conventional tablet or
consequence, organizations are reluctant to capsule dosage form were reformulated into
set up their own softgel manufacturing opera- softgels as a part of an organizations life-cycle
tion in-house and prefer to outsource the management strategy or some other reason
activities to an external softgel contract man- (e.g., Hytrin1, Abbott Laboratories; Claritin1,
ufacturer. Schering-Plough). Some softgel products (e.g.,
(2) Due to the availability of only few contract Zantac1, GlaxoSmithKline) were withdrawn
manufacturing organizations (CMOs) that spe- from the market entirely as they offered no
cialize in the manufacture of pharmaceutical additional advantage over the tablet formula-
quality softgel products (e.g., Pharmaceutics tions. Some additional information on the refor-
International, Inc., Banner Pharmacaps, Inc., mulation efforts of other softgels are presented
Catalent Pharma Solutions, Accucaps Indus- in Table 2.
tries Ltd, Pharmagel Engineering SPA),
lengthy product development and manufactur-
ing lead timelines are not unusual at the When formulation of a compound in a nonaqueous
CMOs. vehicle is shown to be the practical option to achieve
(3) Availability of limited quantities of a compound its acceptable bioavailability (e.g., Neoral1), dictated
during the early stages of development may by its physical nature (i.e., low melting point, oily,
discourage an organization from developing a waxy) (e.g., Depakene1), and/or dictated by its ultra-
softgel product for the compound as an early low to low dose requirements (e.g., Rocaltrol1), the
stage clinical dosage form. probable solid oral dosage form that has good patient
(4) Intellectual property (IP) rights of a CMO on acceptability is the capsule.289 Hard gelatin capsule
the composition of a shell formulation may (HGC) dosage form has been advanced as an alternate
complicate issues related to transferring and to softgel dosage form for encapsulating nonaqueous
manufacturing the softgel product at an alter- liquid and semisolid formulations.289296 There are
nate CMO, especially when a specialized shell substantial differences between the two types gelatin
composition is used in the product. capsules and each dosage form has been shown to
(5) Technically, the high initial water content of have its own advantages and challenges. The choice of
the shell formulation at the time of encapsula- soft gelatin or hard gelatin capsule for encapsulating
tion and subsequent migration of any amount liquids will depend on a variety of factors that will be
of water between the shell and the fill formula- discussed later. First of all, it is useful to discuss
tions could make the softgel dosage form unsui- briefly how a formulation scientist can strategize
table for encapsulating compounds that are various options creatively to overcome some of
4138 GULLAPALLI
the challenges posed by the softgel dosage form thus presence of water in the shells is essential to
development. maintain their integrity. HGC shells must retain a
It is a reasonable approach to separate the softgel moisture content of 1018% to maintain their
dosage form development into two stages: (1) devel- flexibility.299,300 Below this range, the shells become
opment of softgel compatible fill formulation in- brittle and are prone to breakage, while above this
house using knowledge provided in the current range, the shells may deform. Thus, any alteration to
manuscript and other literature and (2) encapsula- this moisture range, due to migration of moisture
tion and scale-up manufacturing of the softgel between the shell and encapsulated fill or between the
product at a CMO using a gel mass of composition shell and external environment, could be detrimental
commonly used across various softgel manufacturers. to the integrity of the HGC shells. In contrast, the
This approach allows an organization to develop the presence of plasticizer(s) in the softgel shell imparts
fill formulation in-house with smaller quantities of elasticity to the shell that allows it to accommodate a
the compound, keep control of its formulation, wide range of hydrophilic excipients. For example,
process, and IP, and also offers the flexibility of polyethylene glycols with molecular weight as low as
manufacturing the final softgel product at more than 400 which are hydrophilic have been successfully
a single manufacturer. Another advantage of this encapsulated into softgels (Tab. 2), whereas HGC
approach is that the fill formulation so developed can shells have been reported to be compatible with
be packaged as a Liquid-In-Bottle (LIB) product and polyethylene glycols with molecular weight higher
used to advance the early phases of a clinical program than 4000.289,296,301 Water and highly hygroscopic
by either encapsulating the liquid into two-piece hard excipients, such as glycerin, sorbitol, propylene
gelatin capsule (Liquid-In-Capsule, LIC) or dispen- glycol, have also been reported to be incompatible
sing unit doses of the liquid into individual containers with the HGC shells at concentrations as low as
for dilution with a compatible vehicle before use.297 5%.291,296 Furthermore, the relatively higher elasti-
The organization can, in the interim, develop an city of the softgel shell resulting from the presence of
alternate dosage form, if feasible, evaluate the option a plasticizer would also provide additional protection
of further development of liquid filled hard gelatin to the softgel product during its handling. On the
capsule (HGC) dosage form, or select softgel CMOs other hand, due to the substantially lower water
and negotiate contracts, if softgel dosage form is the content of the HGC shells, its migration into the fill
only practical option for the compound and to further would be insignificant and thus prevent or minimize
advance the clinical program. Koon298 has provided any water induced crystallization or hydrolytic
some additional tips on selecting a suitable softgel degradation of the dissolved compound encapsulated
contract manufacturer. in the HGC.
When formulation of a compound in a nonaqueous A softgel is a one-piece, hermetically sealed shell
vehicle is shown to be the only practical option, the capsule, which is formed, filled entirely with no
choice to continue with liquid filled HGCs or switch to headspace, and sealed in one operation. In case of
softgels for later stage development and subsequent HGCs, the body of the capsule is filled, capped, and
commercialization is generally determined by two sealed sequentially, leaving substantial headspace
factors. within 10% of capsule volume.292,302 The presence of
Dosage form related: (a) tolerance of capsule shell the headspace within the HGCs may compromise the
towards the fill composition (i.e., hydrophilic or elegance of a product designed with a transparent
lipophilic, type and amount of PEG and cosolvents, shell formulation and the oxidative stability of an
amount of water) and (b) tolerance of fill towards the encapsulated compound. The loss of fillable volume in
shell water content (i.e., crystallization and/or a HGC may also result in a relatively larger capsule
hydrolytic degradation of an encapsulated com- size compared to that of a softgel containing a similar
pound). fill volume.
Encapsulation related: (a) existing in-house devel- As empty HGC shells are supplied ready for use
opment and manufacturing capabilities and person- with various fill volumes292,302 and laboratory scale
nel expertise and (b) ease and cost of setting equipment is also readily available for filling and
capabilities and improving personnel expertise. sealing HGCs,292,295,302 small scale batches of a liquid
Empty hard gelatin capsule (HGC) shells are filled HGC product can be easily manufactured in-
manufactured separately and supplied for encapsu- house using small quantities of a compound for
lating either a powder fill or a liquid fill. HGC shells stability and clinical trial purposes during the early
are generally thinner and lighter than those of stages of drug development. In fact, based on the
softgels and are commonly manufactured from authors experience, these small scale batches can
gelatin, water, a colorant(s), and/or an opacifier. also be manufactured easily using simple equipment,
HGC shells, unlike those of softgels, do not contain a such as a ProFillTM Capsule Filling system (Torpac,
nonvolatile plasticizer (e.g., glycerin, sorbitol) and Inc. http://www.torpac.com/) and a positive displace-
Table 5. Small Scale Softgel Encapsulation Machines
Machine Designation Supplier Die Roll Specificationsa
R&D 4 inch CapPlus Technologies (Phoenix, AZ) Max. die speed5 rpm, die rolls
4 inch long 2.83 inch diameter
RGY6x15F, Pharmaker Machinery (Elmont, NY) Max. die speed4 rpm, die rolls
RGY6x15S 3.94 inch long 2.52 inch diameter
PSG-100 Pharmaland Technology (Ontario, Canada) Max. die speed5 rpm, die rolls
3.94 inch long 2.56 inch diameter
SS-30 Sky Softgel Co. (Incheon, Korea) Max. die speed5 rpm
RG0.8-110 Zhejiang Fuchang Machinery Co. Max. die speed7 rpm, die rolls
(Zhejiang Province, China) 4.33 inch long 2.83 inch diameter
a
Output depends on softgel size and number of cavities and rpm of die roll.
ment pipette. Moreover, unlike softgel manufactur- and/or repair any existing machine parts right away
ing, as there is no need for a time consuming gel mass with minimal loss of time.
preparation and capsule drying process, liquid filled
and sealed HGCs can be manufactured and packaged
within a short time. The readers are directed to the CONCLUSIONS
literature published by Cole et al.,289 Cole,292
Smith,295 and Rowley303 to obtain any further Softgels constitute a unique solid dosage form that
understanding of the manufacturing process for the can be used to conveniently encapsulate nonaqueous
liquid filled HGCs and their characteristics. solution, suspension, and semisolid formulations
R&D scale softgel manufacturing machines have developed to improve the bioavailability of poorly
also been introduced for the production of softgels at a soluble compounds. In addition to several softgel
smaller scale. Some of these machines are commer- products that are already available commercially, the
cially available and offer an organization with the patent literature and the number of softgel products
option to keep its softgel development and manufac- currently under clinical investigations305 clearly
turing activities in-house. Some of the softgel demonstrate that several pharmaceutical and biotech
encapsulation machines available commercially are firms are actively pursuing the softgel dosage form as
presented in Table 5. A laboratory scale encapsula- a choice to formulate compounds with poor biophar-
tion machine (Minicap) mimicking the design of a maceutical properties. The potential of the softgel
standard softgel encapsulation machine, but utilizing dosage form in improving the in vitro and in vivo
a single pocket die design and requiring as little as performance and the physical and chemical stability
50 mL of fill solution has been discussed in the of an encapsulated compound can be maximized
literature.304 The Minicap has been shown to produce through the careful selection of appropriate excipi-
softgels with comparable qualities as those manu- ents in the fill and shell formulations. While the
factured using a standard softgel machine and thus dosage form provides immense promise for a variety
can be used to produce prototype softgels for fill-shell of poorly soluble compounds, its dynamic nature
compatibility screening and stability evaluation. compels the formulation scientist to put in more
However, the Minicap machine, developed by Cardi- efforts than during the development of other conven-
nal Health (currently Catalent Pharma Solutions), tional solid dosage forms, such as tablets and
may not be available for purchase. two-piece hard gelatin capsules. The potential risks
Though softgel manufacturing machines and aux- that may arise during the development and shelf-life
iliary equipment are readily available for purchase, of a softgel product can be managed through the
due to enormous resources required, for example, use of:
designing facilities, sourcing and controlling qualities
of gelatin, optimizing manufacturing process for gel a stable physical form of the drug substance,
mass, acquiring and developing in-house talent and a fill vehicle that minimizes the transfer of water
so on, an organization has to carefully evaluate the from the shell into the fill and/or lessens the
option of establishing softgel manufacturing capabil- effect migrated water on the solubilized state
ities in-house against outsourcing and managing of the drug substance,
the outsourced activities. It is also essential to bear in excipients free from interactions with the drug
mind that the major CMOs that specialize in the substance and/or with each other,
manufacture of softgels have their own in-house excipients free from impurities (e.g., aldehydes,
machine shop capabilities that can build, replace, peroxides) that may adversely effect the gelatin
4140 GULLAPALLI
shell dissolution process and/or the chemical 9. Crew MD, Curatolo WJ, Friesen DT, Gumkowski MJ, Lorenz
stability of the drug substance, DA, Nightlingale JAS, Ruggeri RB, Shanker RM. 2007. Phar-
maceutical compositions of cholesteryl ester transfer protein
plasticizer(s) that minimizes the transfer of com-
inhibitors. US Patent Application 2007/0282009.
ponents from the fill (e.g., ethyl alcohol) or into 10. Stella VJ, Nti-Addae KW. 2007. Prodrug strategies to over-
the fill (e.g., oxygen, moisture), come poor water solubility. Adv Drug Deliv Rev 59:677694.
inert environment during manufacturing, for 11. Merisko-Liversidge E, Liversidge GG, Cooper ER. 2003. Nano-
example, nitrogen blanketing for oxygen sensi- sizing: A formulation approach for poorly-water-soluble com-
tive compounds, yellow light for photosensitive pounds. Eur J Pharm Sci 18:113120.
12. Kipp JE. 2004. The role of solid nanoparticle technology in the
compounds, parenteral delivery of poorly water-soluble drugs. Int J Pharm
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form for some compounds that are highly moisture capsule formulations of terlakiren, a tripeptide rennin inhi-
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ACKNOWLEDGMENTS 2002. A comparison of commonly used polyethoxylated phar-
maceutical excipients on their ability to inhibit P-glycoprotein
The author thanks the Library Staff at Elan Phar- activity in vitro. J Pharm Sci 91:19912002.
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Eur J Pharm Sci 16:237246.
relevant literature to complete the manuscript. The
20. Seeballuck F, Ashford MB, ODriscoll CM. 2003. The
lans IT department for
author also thanks Staff of E effects of pluronics block copolymers and cremophor EL
their assistance in the preparation of figures. on intestinal lipoprotein processing and the potential link
with P-glycoprotein in Caco-2 cells. Pharm Res 20:1085
1092.
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Soft Gelatin Capsules (Softgels)

Received 13 December 2009; revised 15 February 2010; accepted 19 February 2010

INTRODUCTION NCEs coming out of the combinatorial chemistry and

Table 1. Critical Parameters in a Softgel Product Manufacturing

Manufacturing Component Parameter Effects

Absorption of Polyethylene Glycols

Drug Product Information Fill Excipients Properties, Dissolution Method

Drug Product Information Fill Excipients Properties, Dissolution Method

Initial launch as tablet (NDA 17-581;

Drug Product Information Fill Excipients Properties, Dissolution Method

Drug Product Information Fill Excipients Properties, Dissolution Method

Water Mimicking Primary Drying Mimicking Equilibrium

form thermoreversible gel in water, that is, ability to

Glycerin, 20% w/w 11 4.566.44 3.453.81 105

Table 5. Small Scale Softgel Encapsulation Machines

Machine Designation Supplier Die Roll Specificationsa

S-ar putea să vă placă și

Gullapalli, 2009, Soft Gelatin Capsules

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Gullapalli, 2009, Soft Gelatin Capsules

Încărcat de

Drepturi de autor:

Formate disponibile

REVIEW

Soft Gelatin Capsules (Softgels)

Received 13 December 2009; revised 15 February 2010; accepted 19 February 2010

INTRODUCTION NCEs coming out of the combinatorial chemistry and

Table 1. Critical Parameters in a Softgel Product Manufacturing

Manufacturing Component Parameter Effects

Absorption of Polyethylene Glycols

Drug Product Information Fill Excipients Properties, Dissolution Method

Drug Product Information Fill Excipients Properties, Dissolution Method

Initial launch as tablet (NDA 17-581;

Drug Product Information Fill Excipients Properties, Dissolution Method

Drug Product Information Fill Excipients Properties, Dissolution Method

Water Mimicking Primary Drying Mimicking Equilibrium

form thermoreversible gel in water, that is, ability to

Glycerin, 20% w/w 11 4.566.44 3.453.81 105

Table 5. Small Scale Softgel Encapsulation Machines

Machine Designation Supplier Die Roll Specificationsa

S-ar putea să vă placă și

Glycerin, 20% w/w 11 4.566.44 3.453.81 105