POWDERS AND GRANULES As a pharmaceutical preparation, a powder (latin , pulvis) is a mixture of finely divided drugs and / or chemicals in dry

form Powders are subdivided solids which are classified according to the size of their constituent particles which range from <1.25 m to 1.7 mm in diameter. It may be prepared from a naturally occurring dried vegetable drug, or it may be a physical admixture of two or more powdered pure chemical agents. A drug powder may be mixed with other powdered excipients depending upon the intended use of the product. Advantages of powdered products: Are preferred by some patients (infants and young children) who are unable to swallow the solid dosage forms. Stability and shelf-life. Convenient form to dispense drugs with a large dose Faster dissolution and absorption rate than tablet or capsules. Can be applied to many body cavities such as ears, nose, tooth socket, throat Can be made into many different dosage formulations (capsules, tablets, powders for reconstitution, dusting powders, bulk powders, powders for inhalation, etc.) Disadvantages of powders: Less convenient to carry (bulk powder) Masking of unpleasant taste is a problem Potent drug with low dose Not suitable form for drug inactivated in the stomach Difficulty of protecting hygroscopic and deliquescent Or aromatic materials. 1234Dispensed preparations Bulk powders (non toxic medicament with a large dose). Divided powders (separately wrapped) Dusting powders for external use Insufflations (potent drug as: sodium cromoglycate). Oral antibiotic

Preparations requiring further treatment at time of dispensing : syrups Powder for injection

Agglomeration, granulation and pelletizing processes involve the wetting and mechanical handling of particulates. An open and porous agglomerate structure changes to a more closed and grain-like granule structure as the degree of wetting and mixing is increased. Particulates engineering involves the control of moisture and energy input to achieve a desired change in structural and other properties. By improving:

By adjusting:

By reducing:

free floability ease of handling visual appearance ease compaction of

bulk density solubility rate shape and size distribution

fines (dust) content

Particle Size Analysis The particle size of drug and other powders is determined and influences the subsequent physical performance of the medicine and the pharmacological performance of the drug. 123456Particle size influence the production of formulated medicine as solid dosage forms. Powders with different particle size have different flow and packing properties. Flow property& particle size. Particles having small dimensions will tend to increase the rate of dissolution. Particle size influence suspendability of particles intended to remain undissolved but uniformly dispersed in a liquid vehicle Particle size cam\n influence penetrability of particles intended to be inhaled to reach into the respiratory tract. Particle size influences grittiness of solid particles in dermal ointment, cream and ophthalmic preparations.

Methods for determination of particle size: 1Sieving 2Microscopy 3Sedimentation (Andreasen pippett) 4Light energy diffraction 5Laser light scattering 6Electronic sensing zone (Coulter Counter) Powder Flow Reasons for producing freeflowing pharmaceutical powders include: 1Uneven powder flow can result in excess entrapped air within powders which may promote capping or lamination. 2Uneven powder flow can result from excess fine particles in a powder which increase particle-die wall friction, causing lubrication problems, increase dust contamination risks. 3Uniform fed from bulk storage containers into the feed mechanisms of tableting or capsule-filling equipment, allowing uniform particle packing which improve weight uniformity.

Angle of repose: tan = h/r h= the height of the powder cone r= the radius of the powder cone

Cohesion: occurs between like surfaces such as component particles of a bulk solid, Adhesion: occurs between two unlike surfaces, between particle and a hopper wall. Particle size effects Particle shape Particle density Surface texture Porosity Improvement of powder flowability 1Alteration of particle size and size distribution 2Alteration of particle shape and texture 3Alteration of surface forces 4Formulation additives: flow activators 5Moisture control

Blending Powders Depending on: the nature of the ingredients amount of powder equipment available Powders can be blended by: 1Spatulation: for small amounts of powders, there is no reduction in particle size 2Geometric: used to help ensure that small amounts of the ingredients, usually potent drugs, are uniformly distributed throughout the powder mixture. 3Trituration: it gives more intimate mixing than other methods. It describes the grinding of two or more substances in a mortar to intimately mix them. 4Sifting: produce a light fluffy product. 5Tumbling: us a large container which rotates by a motorized process.

Powder Comminuation 12345facilitate crude drug extraction, aid in formulation of pharmaceutically acceptable dosage forms, increase the dissolution rate, enhance the drug absorption, reduce the bulk volume of a material to improve transportation efficiency.

On small scale use mortar and pestles Trituration Levigation I- Cutting methods: Cutter mills For fibrous crude drugs: roots, peels, barks Producing coarse degree of size reduction of dried granulations. II- Impact methods: Hammer mill Vibration mill III- Compression method: Mortar and pestle End-runner and edge runner Mills IV- Attrition method: Roller mill

CAPSULES (Capsula: small box)

Capsules are solid dosage forms in which medicinal agents and /or inert substances are enclosed within a small shell of gelatin. Capsules first appeared in USP XII in 1942. Advantage of encapsulation: Taste concealment (unpleasant taste) Elegance, smooth slippery, easily swallowed shell Nice presentation of the drug Portability, convenient Light weight Rapid drug release Can be used for the extemporaneous compounding of prescriptions.

Capsules are made of hard or soft gelatin shell Hard gelatin capsules

The empty capsule shells are made from a mixture of gelatin, plasticizer, sugar and water (and may contain FD&C dyes and / or opacifying agent, preservative, enteric agent, flavour). Capsules are not suitable: 6

For drugs that are very soluble: as salts (potassium chloride, pot. bromide, ammonium chloride). For efflorescent or deliquescent materials.

Gelatin: is obtained by partial hydrolysis of collagen obtained from bones, skin, connective tissue of animals. 1234Non-toxic, used in food stuff. Readily soluble in biological fluid at body temp. Good film forming material Undergoes a reversible phase change at a little high temp.

Bloom or gel strength of gelatin: It is a measure of the cohesive strength of the cross-linking which occur between the gelatin molecules and is proportional to the molecular weight of the gelatin Bloom is determined by measuring the wt in grams required to move a plastic plunger, 0.5 inches in diameter, 4 mm into a 6.66 % gelatin gel that has been held at 10C for 17 hours. Bloom would be within the range of 150-250 Bloom grams. Viscosity of gelatin also determined on a 6.66% conc. of gelatin in water, is a measure of the molecular chain length and determines the manufacturing characteristics of the gelatin film. The viscosity range for gelatin can be from 25-45 millipoise. Iron is always present in the raw gelatin, gelatin used in the manufacturing of soft gelatin capsules should not contain more than 15% of this element, because its effect on FD&C dyes and possible colour reactions with organic compounds. Plasticizers: Glycerol, sorbitol, propylene glycol.

The ratio by weight of dry plasticizer to dry gelatin determine the harness of the gelatin shell. Colorants Soluble dyes Titanium dioxide Insoluble pigments The oxides of iron

Preservatives Are added to capsules as an in-process aid to prevent microbiological contamination during manufacturing. Sizes of hard gelatin capsule shell: 7

Eight sizes are generally used: No. 5 4 Smallest Volume 0.13 3 0.2 2 0.27 1 0.37 0 0.48 00 0.67 000 largest 0.95 1.36

The capacity of the capsule is dependent on the density and characteristics of the powders in the application. Veterinary capsules are available in sizes No. 10, 11, 12. The capsule size selected should be slightly larger than that needed to hold the powder to provide a full capsule. Capsule fill weight= tapped density of formulation capsule volume All formulations for filling into capsules must: 1be able to accurately dosed into the capsule shell (accurate, ease of filling, elegance). 2release their contents in an available form to the patient (good bioavailability). Types of materials for filling into hard gelatin capsules: 12Dry solid: powders, granules, tablets, pellets Semisolids: pastes, thermosoftening

Formulation factors affecting release from hard gelatin capsules: 1Active ingredient - Solubility - Melting point - Crystalline form - Particle size 2Diluent 3- Glidants and lubricant 4- Wetting Steps for preparation of filled hard gelatin capsules: 1- Developing the formulation and selecting the size capsule. 2- filling the capsule shells. 3- Capsule sealing (optional). 4- Cleansing and polishing the filled capsules. Soft Gelatin Capsules or Soft elastic gelatin (SEG)

Pharmaceutical applications: 1As an oral dosage form for human or veterinary 2As a suppository dosage form for rectal or vaginal use 3As a specialty package in tube form, for single dose application of topical and ophthalmic preparations; rectal ointments; ear and nose drops. Rotary die process machine (Scherer), Iron mold were used for shaping the capsule. SGC are used to hermetically seal and encapsulate liquids, suspensions, pasty materials and dry powders. Advantages of SGC as a dosage form: 1A compression stage is not included. 2The dose content uniformity is optimized, with reduction of the cost through the use of smaller overages. 3Protection of sensitive drug from oxidation and hydrolysis. 4The drug is dissolved or dispersed in vehicle which provide high surface area and good bioavailability. The choice of Plasticizer is related to the type and nature of the capsulated materials while the ratio (hardness of shell) chosen usually is related to the end use of the product or to the geographical area. Plasticizer concentration can be expressed as: parts of dry plasticizer : 1 part of dry gelatin. Range (0.3-1.0) : 1 0.3.0.5 oral products having an oil vehicle 0.4.0.6 oil fill with added surfactant 0.6.1.0 completely water-miscible vehicle, tube shaped, squeeze-out type cap 1.5 vaginal supp The ratio by weight of water to dry gelatin can vary from 0.7-1.3 water to 1.0 part of dry gelatin, depending on the viscosity of the gelatin used.

The nature of the capsule contents: Liquid vehicles: 1water-immiscible, volatile and non-volatile liquids as vegetable and aromatic oils, chlorinated hydrocarbons, ethers 2water-miscible, non-volatile liquids as PEG, and non-ionic surfactants as Tween 80 3water-miscible and relatively non-volatile liquids: alcohol (isopropyl alcohol), propylene glycol and glycerol, polglycerols, sugar esters, glyceryl esters. Suspensions: Insoluble drugs can be dispersed (with suspending agents and surfactants) in the above vehicles or combination of vehicles. Limitation for fill materials: Excipients containing high conc. of water > 5% or other gelatin solvents. Emulsions (o/w or w/o) Extremes of pH: < 2.5 attack gelatin hydrolysis and leakage > 7.5 have a tanning effect on the gelatin Aldehydes, ketones, acid, amines, esters Quality Control Tests for capsules: 1Disintegration tests 2Dissolution tests for capsules 3Weight variations 4Content uniformity (85% - 115 %) 5Moisture permeation test (single-unit and unit-dose container).

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Suppositories Is a medicated solid dosage form intended for use in the rectum, vagina (pessaries). - Latin word : suppositorium Rectal route for drug administration is used when: 1The patient is not able to make use of the oral route. 2The drug is less suited for oral administration 3The drug with an unacceptable taste. Drawbacks of rectal route: 1Slow, incomplete absorption 2Inter, intra-subject variation. 3Large scale production is a problematic Uses of rectal route: iLocal effect (constipation, hemorrhoids) iiSystemic effect (analgesic, antibacterial, antispasmodics, sedative. - The rectum is part of the colon, ends with a circular muscle, the anus. - The total volume of mucus is 3 ml. Factors affecting absorption from the rectum: 1- Physiological factors: - Fluid available - Properties of rectal fluid - Content of the rectum - Motility of the rectal wall 2- Physicochemical characteristics of drug: - Lipid/water partition coefficient - Drug particle size - Degree of ionization - Amount of drug Drug in vehicle rectal mucosa. drug in colon fluid absorption through the

Formulation of suppositories: Supp. are in different shapes, sizes 1- 4 g Adult supp. 2g Children supp. 1g Vaginal supp. (globular, oviform shape) 3-5 g Types of suppository base: 1Glycerides-type fatty bases 2Water-soluble bases

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Requirements of the optimum base: 1Melt at, or just below body temp. or dissolve in body fluid 2Rapid solidification after preparation 3Be miscible with many ingredients 4Non-toxic, non-irritant 5Resistant to handling 6Enough volume of contraction to permit removal from the mould 7Stable on heating above its m.p 8Low acid value, low iodine value 9Physically, chemically stable on storage 10- With high water number Fatty vehicles (bases) Natural: Cocoa butter (Theobroma oil) It is a yellowish-white, solid, brittle fat, smells and tastes like chocolate Character of cocoa butter supp base: 1Non-irritant, bland 2Smells and tastes like chocolate 3Miscible with many ingredients 4Rapid melting, rapid solidification when cooled 5Melting range 30-35 C (solid at R.T.) 6Iodine value 34-38 (rancidity) 7Acid value < 5 Disadvantage of cocoa butter as a supp. base: 1It exhibits marked polymorphism, this is attributed to the high proportion of unsaturated triglycerides. form, melting at 24 C, form m.p 28-31 C, stable , melts 34-35 C, form, melting at 18 C Prolonged heating above the critical temp. 35 C causes the formation of the unstable crystals with resulting lowered m.p. 2It can rancidify (unsat. Fatty acid, oleic acid) 3Insufficient contraction at cooling, so lubrication is important. 4Poor water absorptive power 5Some drugs as volatile oils, phenol, chloral hydrate lower the m.p of cocoa butter. Addition of wax and spermaceti can correct this condition. 7 parts of cocoa butter and 1 part of spermaceti. Synthetics fats Vegetable oils are modified by esterification, hydrogenation and fractionation at different melting range to obtain the desired product. Semi synthetic type of fatty vehicles (termed adeps solidus). Composed of mixed triglycerides of saturated fatty acid and mono, diglycerides. Witepsol H15, Witepsol W35, Suppocires Lubrication of mold is unnecessary, not affected by overheating. Appreciable quantities of aqueous solution can be incorporated 12

m.p Cocoa butter Adeps solidus 31-34 C 33-37.5C

Acid content <5 <2

Hydroxyl no 0 < 5-30

Iodine no 34-38 <3

Disadvantage: 1These bases become brittle if cooled too rapid 2The viscosity of the synthetic fats, is lower than that of cocoa butter, there is a great risk of the active ingredients sedimentation during preparation, leading to a lack of uniformity. Water-soluble vehicles They comprise the classical glycerol-gelatin or soap bases, PEG. 1- Glycerinated gelatin glycerol 70% gelatin 20% purified water to 100% It dissolves in the rectal fluid rather than melted. Is a useful suppository base for vaginal use. It is suitable for use with a wide range of medicaments: alkaloids, boric acid, zinc oxide, ichthammol. Glycerinated gelatin supp. are translucent, resilient and gelatinous solids. Mold calibration 1.2 g of base occupy the same volume a 1g cocoa butter base. It must be kept in well-closed containers in a cool place, a preservative should be added 2- Polyethylene glycol polymers (Macrogols) May be used singly or two or more PEGs with different M.Wt mixed in various proportions to yield product of satisfactory hardness and dissolution time. They are chemically stable, miscible with water, they may be safely stored at room temp. they will not support mould growth, no laxative effect. Disadvantages of PEGs supp. base: i- They are hygroscopic, attract water resulting in a painful sensation for a patient (add 10% water during manufacture). ii- Incompatible with several drugs, plastics. iii-Become brittle if cooled rapidly and on storage iv- Crystal growth may cause irritation (waxy coat or local anesthetic may be used). Methods of preparation: 1- Fusion molding (density calculations and mold calibrations are required) Density factor = weight of drug weight of base displaced 13

Displacement value: is the number of parts by weight of drug which displaces 1 part by weight of the base. 2- Compression molding: preparation of supp. from grated mass of supp. base and medicaments which is forced into a special compression mold. This method avoids the sedimentation of insoluble solids in the supp base, it is too slow for large scale production. Dispensing supp. In boxes lined with waxed paper or in plastic container Or separately wrapped in metal foil. Labeling supp. "Store in a cool place" "For rectal use only" Don't swallow Suppositories Specific problems in formulating suppositories

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Moisture in suppositories Hygroscopicity Glycerinated gelatin and polyethylene glycol Incompatibilities ( PEG) Viscosity (sedimentation of suspended particles, 2% aluminum monostearate, cetyl, stearyl or myristyl alcohols o stearic acid are added to improve the consistency of suppositories). Brittleness (Tween 80, glycerin, propylene glycol impart plasticity). Volume contraction Lubricants or mold release agents Rancidity & antioxidants

Quality control test for suppositories: 1- Appearance 6- Content uniformity 2- Disintegration 7- Mechanical strength 3- Weight variation 4- Melting behaviour 5- Drug release

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