Taibah University College of Pharmacy Pharmaceutics III PPT 343 PDF

Taibah University College of Pharmacy Department of Pharmaceutics & Pharmaceutical Industries Pharmaceutics III PPT 343 Solid and Semisolid Dosage...

Taibah University College of Pharmacy Department of Pharmaceutics & Pharmaceutical Industries Pharmaceutics III PPT 343 Solid and Semisolid Dosage Forms Collected and reviewed by Dr. Nader Namazi Sources: Aulton, M, E. (2013), Aulton’s Pharmaceutics, The Design and manufacture of medicines, Fourth Edition, Churchill Livingstone, Elsevier, UK. 0  Table of Content Lecture Topic P 1 Powders and granules 3 2 Tablets types and manufacturing. 11 3 Tablet coating 29 4 Controlled release tablets 34 5 Filling and manufacturing of hard and soft gelatin capsules. 45 6 Suppositories 7 Semisolid preparations 1  Taibah University College of Pharmacy Department of Pharmaceutics & Pharmaceutical Technology Pharmaceutics III PPT 343 Solid and Semisolid Dosage Forms Collected by Dr. Nader Namazi Sources: Kevin Taylor, Michael Aulton (2013) Aulton's Pharmaceutics: The Design and Manufacture of Medicines. 4th Ed. Part 4: Biopharmaceutical Principles of Drug Delivery (Pages 292-295) 2  Suppositories Suppositories are solid dosage forms intended for insertion into body orifices where they melt, soften, or dissolve and exert localized or systemic effects. Route of administration: Suppositories are commonly employed: Rectally Vaginally Occasionally urethral The shape and size must be such that it is: - Easily inserted into the intended body orifice without causing excessive distension. - Once inserted, it must be retained for the appropriate period of time. Advantages of suppositories 1. Precise dosage forms containing accurate quantities of medicament(s). 2. Used for systemic distribution when the oral administration was not suitable. As in unconscious patients. 3. Simplify or eliminate the problem of medication. 4. Administration of some medicaments, which are not tolerated orally. e.g. medicaments which are sensitive to the gastric pH and gastric enzymes. 5. Administration of medicament that interrupt the function of the gastrointestinal tract e.g. drugs irritating to the stomach. 6. Useful when the stomach is not the ideal position to receive medication. Such as in case of nausea and vomiting. 7. Suitable when local effect is wanted as in the treatment of rectal, vaginal and urethral diseases. 8. Faster onset of action than found after oral administration. As the drug is directly absorbed from the mucosa into the venous circulation. 4  9. Drugs destroyed by portal circulation may by pass the liver circulation, where many drugs subject to metabolic changes (first pass effect). Rectal suppositories For adults weigh 2 g. Torpedo in shape. Children's suppositories weigh about 1 g. Vaginal suppositories Also called “ Pessaries ” Weigh about 3-5 g Molded in globular or oviform shape or compressed on a tablet press into conical shapes. Urethral suppositories Called “ bougies ” and are pencil shape. For males are 4 g each. For females are 2 g each. Other Vaginal or Rectal Dosage Forms: Vaginal Tablets (Inserts): At the present, vaginal tablets are more widely used than vaginal suppositories. Advantages of Vaginal Inserts: More stable, easier to manufacture. Less messy to handle because they do not have fatty or waxy bases. More convenient in use, supplied with a plastic inserter. They disintegrate and disperse vaginally in the secretions and slowly release the medicament. Vaginal inserts may be momentarily dipped in worm water just prior to use to facilitate its insertion and dispersion in the vagina. They are prepared by tablet compression from granulation composed of lactose as a vehicle, starch as a disintegrant. They are available in the form of hard or soft gelatin capsules. Rectal and vaginal ointments and creams are commonly used to relieve local conditions. Vaginal, ointments and creams usually contain antimicrobial agents, estrogenic hormonal substances or contraceptive agents. 5  N.B. Rectal and vaginal ointments are generally provided with special applicator. Aerosol foams are commercially available containing estrogenic substances or contraceptive agents. The foams are usually O/W emulsions (light creams). They are water miscible and non greasy. Disadvantages of Suppositories 1. The problem of patient acceptability. 2. Suppositories are not suitable for patients suffering from diarrhea. 3. In some cases the total amount of the drug must be given will be either too irritating or in greater amount than reasonably can be placed into suppository. 4. Incomplete absorption may be obtained because suppository usually promotes evacuation of the bowel. Indications The use of suppositories is indicated under the following circumstances: To empty the bowel before certain types of surgery. To empty the bowel to relieve acute constipation or when other treatments for constipation have failed. To empty the bowel before endoscopic examination. The use of suppositories is indicated under the following circumstances: To introduce medication into the system. To soothe and treat haemorrhoids or anal pruritus. Contraindications The use of suppositories is contraindicated when one or more of the following pertain: Chronic constipation, which would require repetitive use. Paralytic ileus. Colonic obstruction. 6  Following gastrointestinal or gynecological operations, unless on the specific instructions of the doctor. The rectum Anatomy of the rectum: The rectum is part of the colon, forming the last 15 – 20 cm of the GI tract. The rectum can be considered as a hollow organ with a relatively flat wall surface, without villi. It contains only 2 – 3 ml of inert mucous fluid with pH of 7.5. Factors Affecting the Rectal Absorption Physiological factors Colonic content Circulation route pH and lack of buffering capacity of the rectal fluids. Physicochemical factors of the drug & the base Lipid-water solubility. Particle size Nature of the base. Physiological factors Colonic content Greater absorption may be expected from a rectum that is void than from one that is distended with fecal matter. This is because the drug will obviously have greater opportunity to make contact with the absorbing surface of the rectum and colon in the absence of fecal matter. 7 Other conditions such as diarrhea, colonic obstruction due to tumorous growths and tissue dehydration can all influence the rate and degree of drug absorption from the rectal site. Circulation route: Drugs absorbed rectally, unlike those absorbed after oral administration, bypass the portal circulation during their first pass into the general circulation. Thereby enabling drugs destroyed in the liver to exert systemic effects. The lower hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its circulation throughout the body. Lymphatic circulation also assists in the absorption of rectally administered drugs. pH and lack of buffering capacity of the rectal fluids For systemic drug action, it is preferable to incorporate the ionized rather than the unionized form of a drug in order to maximize bioavailability. Physicochemical factors of the drug & the base Lipid-water solubility The lipid-water partition coefficient of a drug is an important Factor for: Selection of the suppository base. Anticipation of drug release from the base. A lipophilic drug that is distributed in a fatty suppository base in low concentration has less of a tendency to escape to the surrounding aqueous fluids than would a hydrophilic substance present in a fatty base to an extent approaching its saturation. Water-soluble bases, for example, polyethylene glycols which dissolve in the anorectal fluids, release for absorption both water-soluble and oil-soluble drugs. Naturally, the more drug a base contains, the more drug will be available for potential absorption. 8 However, if the concentration of a drug in the intestinal lumen is above a particular amount, the rate of absorption is not changed by a further increase in the concentration of the drug. Particle size For drugs present in the suppository in the un-dissolved state, the size of the drug particle will influence its rate of dissolution and its availability for absorption. The smaller the particle size, the more readily the dissolution of the particle and the greater the chance for rapid absorption. Nature of the base The base must be capable of melting, softening, or dissolving to release its drug components for absorption. If the base interacts with the drug inhibiting its release, drug absorption will be impaired or even prevented. If the base is irritating to the mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement, opposing the prospect of a systematic drug release and absorption. Suppository Bases Function of Suppository Bases: Dilute the drug to nonirritating level, Control the rate of drug release and Represent the drug in an acceptable usable form. Specification for suppository Bases: Origin and chemical composition. 9 A brief description of the composition of the base reveals the source of origin (i.e., either entirely natural or synthetic, or modified natural products) and chemical makeup CH3(CH2)15CH2COOH + KOH → CH3(CH2)15CH2COOK + H2O Acid Value: Is the amount of free acid present in fat as measured by the milligrams of potassium hydroxide needed to neutralize it. Iodine Value: is the mass of iodine in grams that is consumed by 100 grams of fat or unsaturated materials. One application of the iodine number is the determination of the amount of unsaturation contained in fatty acids. Saponification Value: Represents the number of milligrams of potassium hydroxide required to neutralize the free acids and saponify 1g of fat. It is a measure of the average molecular weight (or chain length) of all the fatty acids present. Melting Range. Since fatty suppository bases are complex mixtures of triglycerides and therefore do not have sharp melting points, their melting characteristics are expressed as a range indicating the temperature at which the fat starts to melt and the temperature at which it is completely melted. Water Number. It is the amount of water, in grams, that can be incorporated in 100 g of fat. The "water number" can be increased by the addition of surface active agents, monoglycerides, and other emulsifiers. Solidification Point. 10 the time required for solidifying the base when it is chilled in the mould. If the interval between the melting range and solidification point is 10°C or more, the time required for solidification may have to be shortened by refrigeration to produce a more efficient manufacturing procedure. The ideal suppository base may be described as follows: Melts at rectal temperature 37.5 ºC. Nontoxic and non-irritating to sensitive and inflamed tissues. Compatible with a broad variety of drugs. No meta-stable forms Shrinks sufficiently on cooling to release itself from the mould without the need for mould lubricants. Non sensitizing, Stable on storage, and has wetting and emulsifying properties., Has a high "Water number“, "Acid value" is below 0.2, "Saponification value" ranges from 200 to 245,and “Iodine value” is less than 7. Can be manufactured by moulding. Small interval between melting point and solidification point. Types of Suppository bases: Oily or fatty bases a. Cocoa Butter (Theobroma Oil) b. Emulsified Theobroma Oil c. Synthetic Hard Fat (Hydrogenated Oils) Hydrophilic bases 1. Glycerinated gelatin 2. The Polyethylene Glycols (Macrogols) 3. Soap glycerine Water dispersible bases 11  Emulsifying bases Cocoa Butter (Theobroma Oil) It is the most widely used suppository base. It is often used in compounding prescription when no base is specified as it satisfies many of the requirements for an ideal base. Cocoa butter is defined as the fat obtained from roasted seed of Theobroma cacao. Chemically, it is primarily a triglyceride of oleo-palmito-stearin and oleo- distearin predominate. It is a yellowish-white, solid, brittle fat, which smells and tastes like chocolate. Because cocoa butter can easily melt and rancidify, it must be stored in cool, dry place, and protected from light. Advantages of Cocoa Butter (Theobroma Oil) A melting point range of 34-38°C (i.e. solid at normal room temperature but melts in the body). Readily melted on warming, rapid setting on cooling. Miscible with many ingredients. Non-reactive and non-irritating Disadvantages of Cocoa Butter (Theobroma Oil) 1.Adhesion to the mould. may be overcome by adequate lubrication. 2.Rancid on storage due to oxidation of unsaturated glycerides. 3. Softening point is too low for hot climate. 4. Melting point reduced by soluble ingredients.Additives such as beeswax may be incorporated to raise the melting point sufficiently to counteract the effects of medicaments and/or climate. 5. Poor water absorbing ability. Improved by the addition of emulsifying agents. 6. Leakage from the body. Sometimes melted base escape from the rectum or vagina, for this reason, oil of theobroma is rarely used as a pessary base. 12 7. Expense. 8. Polymorphism Polymorphism Cocoa Butter Cocoa butter exhibits marked poly-morphism (the property of existing in different crystalline forms). Each of the different crystalline forms of cocoa butter has different melting points, as well as different drug release rates. Cocoa butter is thought to be capable of existing in four crystalline states: 1. The α form, melting at 24ºC, is obtained by suddenly cooling melted cocoa butter to 0ºC. 2. The β' form crystallizes out of the liquefied cocoa butter with stirring at 18 - 23ºC. Its melting point lies between 28 and 31ºC. 3. The β' form changes slowly into the stable β form, which melts between 34ºC and 35ºC. This change is accompanied by a volume contraction. 4. The γ form, melting at 18ºC, is obtained by pouring cool (20ºC) cocoa butter into a container, which is closed at deep-freeze temperature. N.B : β form is the most stable one. The formation of the unstable forms can be avoided by various methods: If the mass is not completely melted, the remaining crystals prevent the formation of the unstable form. Small amounts of stable crystals, added to the melted cocoa butter, accelerate the change from the unstable to the stable form; this process is called "seeding". The solidified melt is preserved at temperatures between 28°C and 32°C for hours or days, causing a comparatively quick change from the unstable to the stable form. Emulsified theobroma oil Several agents are used to form emulsified theobroma oil suppositories: why?? To promote the diffusion of the medicinal agent to the surrounding tissue and its subsequent absorption. 13  Makes melting unnecessary since the suppository will swell and disintegrate in the presence of moisture and incorporate more aqueous solution. Thus, the melting point may be raised without fear of interfering with disintegration. Example: The addition of 5 % glyceryl monostearate, or 2 % lecithin or 2% cholesterol has been recommended for preparing emulsified cocoa butter suppositories. Synthetic hard fat (hydrogenated oils) Synthetic hard fat bases are prepared by: First hydrolyzing the vegetable oil. Hydrogenating the resulting fatty acids. Re-emulsifying the acids by heating with glycerol. Advantages over theobroma oil Their solidification points are unaffected by overheating. They have good resistance to oxidation because their unsaturated fatty acids have been reduced. The difference between melting and setting points is small, generally only 1.5-2°C and seldom over 3°C. When the setting point of a base is well below the melting point, the suppositories soften quickly when handled and become too slippery to administer. They usually contain a proportion of partial glycerides some of which, e.g. glyceryl monostearate, are w/o emulsifying agents and, therefore, their water-absorbing capacities are good. Mould lubrication is unnecessary as they contract significantly on cooling. They produce suppositories that are white and almost odorless and have an attractive, clean, polished appearance. Disadvantages over theobroma oil Low viscosity when melted allowing sedimentation of suspended ingredients at the melted stage. This problem can be avoided by the use of thickeners. 14  Brittle if cooled rapidly (avoid refrigeration) Hydrophilic bases Glycerinated Gelatin It has many properties that make it a desirable base for suppositories. Foremost among these is its hydrophilic character. Glycerinated gelatin may be used to prepare all types of suppositories and it is particularly useful in vaginal suppositories. It is well adapted for the incorporation of solid extracts such as belladonna. N.B: Suppositories made with glycerinated gelatin slowly dissolve in the aqueous secretions and provide a slow, continuous release of medication. There are two major types of gelatin, each of which has its specific applications. 1. Type A (Pharmagel A) Derived from an acid-treated precursor and has a pH between 3.8 - 4.5. It carries a strong +ve charge and behaves as a cationic agent. has an isoelectric point between pH 7 and 9 2. Type B (Pharmagel B) It is made from an alkali-treated precursor and has a pH between 5 -7. its isoelectric point (pH 4.7 to 5), It carries a -ve charge and behaves as an anionic agent and it contains small amounts of calcium and usually, phosphates. N.B: The type of gelatin selected must be based upon the properties of the medicament to be incorporated. e.g. It was found that ichthammol suppositories made with type A gelatin were granular. This is explained by the known incompatibility of ichthammol and acids 15 Many formulae have been recommended for glycerinated gelatin, differing in the proportion of glycerin, gelatin, and water. B.P.C. U.S.P. E.P. Gelatin 25 20 14 Glycerin 40 70 70 Water to 100 100 100 Glycerinated gelatin is the best vehicle for the effective use of antiseptics such as hexyl resorcinol. The base does not melt at body temperature, but rather dissolve in the secretions of the cavity in which they are inserted. Solution time is regulated by: 1. The proportion of gelatin : glycerin : water used. 2. The nature of gelatin used. 3. The chemical reaction of the drug with gelatin. The consistency of a 20 % gelatin formula was found inadequate for rectal use. Gelatin content is sometimes increased to as high as 30%. Another procedure for firmer consistency is to replace a portion of the water or glycerin with mucilage of acacia. For urethral suppositories: Gelatin 60% Glycerin 20% Medicated aqueous portion 20% Disadvantages of Glycerinated Gelatin Glycerol suppositories have laxative action. Unpredictable solution time. Varies with the batch of gelatin and the age of the base. 16  Hygroscopic. Requires protection from heat and moisture and has a dehydrating effect on the mucosa leading to irritation. Microbial contamination. require preservation leading to problems of incompatibility. Long preparation time. The base is more time consuming to prepare than fatty bases and may be difficult to remove from the mould. Lubrication of the mould is essential. Polyethylene glycols (Macrogols) Polyethylene glycols are polymers of ethylene oxide and water, prepared to various chain length, molecular weights, and physical states. Polyglycols Physical state: The lower molecular weight compounds, e.g. 400 and 600 (average molecular weights) are liquids, 1000 has the consistency of ointment, 3000- 6000 are white wax solids. Their water solubility and hygroscopicity decrease with increasing average molecular weights. The polyethylene glycol suppositories can be prepared by both molding and cold compression methods. Several combinations of polyethylene glycols have been prepared for suppository bases having desired consistency and different physical characteristics. BASE (1) Polyethylene glycol 1000 96% Polyethylene glycol 4000 4% low melting point and may require refrigeration during the summer months. It is useful if rapid disintegration is desired. It is recommended for suppositories that are intended to be used in a reasonably short time after preparation. BASE (2) Polyethylene glycol 1000 75% Polyethylene glycol 4000 25% 17  This base is more stable than base (1) and may be subjected to storage at higher temperatures than the previous one. It is useful when a slow release of active ingredients is preferred. BASE (3) Polyethylene glycol 1540 70% Polyethylene glycol 6000 30% The purpose for this base is to accommodate these drugs which lower the melting point of the polyethylene glycols. Peru Balsam, ichthammol, sulphanilaimde, tannic acid, chloral hydrate, salicyline acid, and aspirin are examples of such medicinal substances. BASE (4) Polyethylene glycol 6000 50% Polyethylene glycol 1540 30% Water and Medication 20% Base (4) contains water to facilitate the incorporation of water-soluble, polyethylene glycol-insoluble substances, such as sodium Phenobarbital, mild silver protein and mercurochrome. Advantages of Macrogols: Microbial contamination is less likely. Preparation is convenient. The base contracts slightly on cooling and no lubricant is necessary. c. Good solvent properties. d. Give product with clean smooth appearance e. Melting point generally above body temperature. Cool storage is therefore not so critical; they are suitable for hot climates and less likely to melt on handling. The bases do not melt in the body but dissolve and disperse the medication slowly, providing a sustained effect. 18 Disadvantages of Macrogols: Hygroscopic: Like glycero-gelatin base, polyethylene glycol bases may cause irritation to the mucosa. Overcome by the incorporation of 20% water in the mass or by instructing the patient to dip the preparation in water prior to insertion. Poor bioavailability of medicaments may result in retention of the drug in the liquefied base with consequence reduction in therapeutic effect. 3.Crystal growth of certain medicaments may occur. if they are partly in solution or suspension in the base In addition to making the product brittle (fragile), the crystals may be irritant and, because they are large, take longer to dissolve. Brittleness (unless poured at as low temperature as possible) The addition of surface-active agents or plasticizer may reduce brittleness. One cause is the high solubility of the macrogols, which can lead to a supersaturated solution in the water and subsequent crystallization. 5. Incompatibilities with some medicaments, e.g. bismuth salts, ichthamol, benzocaine and phenol Reduces the activity of quaternary ammonium compounds. Interact with some plastics which limits the choice of container. Soap Glycerin Stearin soap (sodium stearate) is used as a suppository base. The soap used in this base is formed in glycerin solution by interaction between stearic acid and sodium carbonate. It has certain advantages over gelatin for making glycerin sufficiently hard for suppositories. A larger quantity of glycerin can be incorporated actually up to 95% of the mass. Soap assists the action of glycerin, whereas gelatin dose not. Soap glycerol suppositories have laxative action. The disadvantage is that soap glycerin suppositories are very hygroscopic, and require to be wrapped in waxed paper or pure tin foil, and protected from the atmosphere. 19  Water Dispersible bases Several non-ionic surfactants, closely related chemically to the polyethylene glycols, have been developed as suppository vehicles. Surfactants used: Many of these bases can be used alone or in combination with other suppository bases for formulating both water-soluble and oil-soluble drugs. Examples: Tween, Myrj, and Span. Caution must be exercised in the use of surfactants with drugs. There are reports indicating increased rate of drug absorption and other reports showing interaction of these surfactants with drugs and a consequent decrease in therapeutic activity. Emulsifying Bases A) Massa Estrinum (Adeps Solidus) This is a mixture of the monoglycerides, diglycerides, and triglycerides of the saturated fatty acids having the formula C11H23COOH to C17H35COOH. Several grades to suit climate changes such as Massa estrinum A, AB, AS, B, BB, BC, BD and C with a melting range of 33 to 38°C. B) Massupol It consists of glyceryl esters mainly of lauric acid, to which a small amount of glyceryl monostearate has been added to improve its water absorbing capacity C) Witepsol 20 They consist of hydrogenated triglycerides of lauric acid with added monoglycerides. Nine grades of Witepsol Hl2, Hl5, W35, S55, E75 and E55 are in common uses. They are suitable for formulation of eutectic mixtures and tropical suppositories. Difference between Witepsol and Cocoa butter Witepsol enables the suppository to ascend more in the rectum before disintegration, while a cocoa butter suppository, melting more rapidly at a lower temperature and more likely to cause leakage. Unlike cocoa butter, the Witepsols are not subject to structural changes at temperatures above their melting points (polymorphism). They absorb water, due to the presence of glycerol mono and diesters as emulsifiers. The interval between softening and melting is small and the masses congeal just one or two degrees below their softening points. Witepsols solidify rapidly after being poured at their melting temperature into the mould and chilling of the mold is unnecessary. Witepsols contract more upon solidification than cacao butter, thus eliminating the need for lubricating the mould. Combinations of Witepsol HI5 and E85 cover a wide melting point range. D) Wecobee Bases used in the preparation of suppositories are triglycerides that are derived from: A. Coconut oil B. Palm oil C. Mineral oil D. Almond oil E. Olive oil E) Dehydraz Bases F) Emulsified Propylene Glycol Derivatives Propylene glycol α-monostearate (monolene) was developed as a suppository base. This base melts within body temperature and it is self-emulsifying in water, forming soft bulky non-irritant emulsion, suitable for rectal treatment. Advantages of Emulsifying Bases 21  The physical characteristics are not altered by overheating. They do not adhere to the mould, which needs no lubricant. Indeed, lubrication is a disadvantage as it may spoil the glossy appearance of the product. They solidify rapidly. As they all contain an emulsifying agent, they can absorb fairly high percentages of aqueous liquids. The emulsifying agents are monoglycerides which form water-in-oil emulsions and this would seem more rational than the use of oil-in-water emulsifying agents Methods of Preparing Suppositories 1. Hand molding It is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base. Steps: A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape. Advantage of hand molding method: 1. Avoiding the necessity of heating the cocoa butter. Disadvantage of hand molding method: Effective hand rolling requires considerable practice and skill. The suppository "pipe" or cylinder tends to crack or hollow in the center;" especially when the mass is insufficiently kneaded and softened. 2. Compression Molding It is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold. 22  The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients. 3. Fusion Molding It involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. The mixture is removed from the heat and poured into a suppository mold. When the mixture has congealed, the suppositories are removed from the mold. The fusion method can be used with all types of suppositories and must be used with most of them. Semisolids Preparations Introduction Structure of the skin Structurally, the skin is composed of three layers: The epidermis: made up of stratified, vascular and cellular layers The dermis: Connective tissue layer Subcutaneous fat layer 23