Design of Dosage Forms PDF

1 Design of dosage forms Peter York...

1 Design of dosage forms Peter York CHAPTER CONTENTS of drug substances to form various medicines or Principles of dosage form design...... 6 dosage forms. The principal objective of dosage form design is to Biopharmaceutical aspects of dosage form design................. 8 achieve a predictable therapeutic response to a drug Routes of drug administration.......... 9 included in a formulation which can be manufactured on a large scale with reproducible product quality. To Drug factors in dosage form design.... 11 ensure product quality, numerous features are required: Particle size and surface area......... 12 chemical and physical stability, with suitable preserva- Solubility.................... 12 tion against microbial contamination if appropriate, Dissolution................... 13 uniformity of the dose of the drug, acceptability to Partition coefficient and pKa.......... 14 users, including both prescriber and patient, and suitable Crystal properties: polymorphism....... 14 packaging and labelling. Ideally, dosage forms should Stability.................... 15 also be independent of patient-to-patient variation, Organoleptic properties............ 15 although in practice this feature remains difficult to Other drug properties............. 16 achieve. However, recent developments are beginning Therapeutic considerations in dosage to accommodate this requirement. These include drug form design.................16 delivery systems that rely on the specific metabolic Summary.................. 17 activity of individual patients and implants that respond, Bibliography.................17 for example, to externally applied sound or magnetic fields to trigger a drug delivery function. Consideration should be given to differences in Principles of dosage the bioavailability of drugs (the rate and extent to form design which they are absorbed) and their biological fate in patients between apparently similar formulations and Drugs are rarely administered as pure chemical possible causative reasons. In recent years, increasing Copyright © 2017. Elsevier. All rights reserved. substances alone and are almost always given as attention has therefore been directed towards elimina- formulated preparations or medicines. These can tion of variation in bioavailability characteristics, range from relatively simple solutions to complex particularly for medicinal products containing an drug delivery systems through the use of appropri- equivalent dose of a drug substance, as it is recognized ate additives or excipients in the formulations. The that formulation factors can influence their therapeutic excipients provide varied and specialized pharma- performance. To optimize the bioavailability of drug ceutical functions. It is the formulation additives substances, it is often necessary to carefully select that, amongst other things, solubilize, suspend, the most appropriate chemical form of the drug. For thicken, preserve, emulsify, modify dissolution, example, such selection should address solubility increase the compactability and improve the flavour requirements, drug particle size and drug physical 6 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  Design of dosage forms CHAPTER 1 Table 1.1 Dosage forms available for different chemical forms and formulation additives, a range of administration routes effective anti-inflammatory preparations are available, including tablets, gastro-resistant coated tablets, Administration Dosage forms injections, eye drops and enemas. The extremely route low aqueous solubility of the base prednisolone and Oral Solutions, syrups, suspensions, emulsions, its acetate salt makes these forms useful in tablet and gels, powders, granules, capsules, tablets slowly absorbed intramuscular suspension injection Rectal Suppositories, ointments, creams, forms, whilst the soluble sodium phosphate salt enables powders, solutions preparation of a soluble tablet form and solutions for eye and ear drops, enemas and intravenous injections. Topical Ointments, creams, pastes, lotions, gels, The analgesic paracetamol is also available in a range solutions, topical aerosols, foams, transdermal patches of dosage forms and strengths to meet the specific needs of the user, including tablets, dispersible tablets, Parenteral Injections (solution, suspension, emulsion paediatric soluble tablets, paediatric oral solution, forms), implants, irrigation and dialysis sugar-free oral solution, oral suspension, double- solutions strength oral suspension and suppositories. Respiratory Aerosols (solution, suspension, emulsion, In addition, whilst many new drugs based on low powder forms), inhalations, sprays, gases molecular weight organic compounds continue to be Nasal Solutions, inhalations discovered and transformed into medicinal products, Eye Solutions, ointments, creams the development of drugs from biotechnology is increasing and the importance of these therapeutic Ear Solutions, suspensions, ointments, creams agents is growing. Such active compounds are mac- romolecular and of relatively high molecular weight, form and should consider appropriate additives and and include materials such as peptides, proteins and manufacturing aids coupled with selection of the most viral components. These drug substances present appropriate administration route(s) and dosage different and complex challenges in their formulation form(s). Additionally, suitable manufacturing pro- and processing into medicines because of their alterna- cesses, labelling and packaging are required. tive biological, chemical and structural properties. There are numerous dosage forms into which a Nevertheless, the underlying principles of dosage drug substance can be incorporated for the convenient form design remain applicable. and efficacious treatment of a disease. Dosage forms At present, these therapeutic agents are principally can be designed for administration by a variety of formulated into parenteral and respiratory dosage delivery routes to maximize therapeutic response. forms, although other routes of administration are Preparations can be taken orally or injected, as well being considered and researched. Delivery of these as being applied to the skin or inhaled; Table 1.1 lists biotechnologically based drug substances via these the range of dosage forms which can be used to routes of administration imposes additional con- deliver drugs by the various administration routes. straints on the selection of appropriate formulation However, it is necessary to relate the drug substance excipients. to the clinical indication being treated before the Another growing area of clinically important correct combination of drug and dosage form can be medicines is that of polymer therapeutics. These agents made, as each disease or illness often requires a include designed macromolecular drugs, polymer–drug specific type of drug therapy. In addition, factors and polymer–protein conjugates as nanomedicines, Copyright © 2017. Elsevier. All rights reserved. governing the choice of administration route and the generally in injection form. These agents can also provide specific requirements of that route which affect drug drug-targeting features (e.g. treating specific cancers) absorption need to be taken into account when dosage as well as modified pharmacokinetic profiles (e.g. forms are being designed. changed drug metabolism and elimination kinetics). Many drugs are formulated into several dosage It is therefore apparent that before a drug substance forms of various strengths, each having selected can be successfully formulated into a dosage form, pharmaceutical characteristics which are suitable for a many factors must be considered. These can be specific application. One such drug is the glucocorticoid broadly grouped into three categories: prednisolone used in the suppression of inflammatory 1. biopharmaceutical considerations, including and allergic disorders. Through the use of different factors affecting the absorption of the drug 7 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  CHAPTER 1  substance from different administration as drug distribution, metabolism and excretion. In routes; general, a drug substance must be in solution before 2. drug factors, such as the physical and chemical it can be absorbed via absorbing membranes and properties of the drug substance; and epithelia of the skin, gastrointestinal tract and lungs 3. therapeutic considerations, including into body fluids. Drugs are absorbed in two general consideration of the clinical indication to be ways: by passive diffusion and by carrier-mediated treated and patient factors. transport mechanisms. In passive diffusion, which is thought to control the absorption of many drugs, the High-quality and efficacious medicines will be for- process is driven by the concentration gradient existing mulated and prepared only when all these factors across the cellular barrier, with drug molecules passing are considered and related to each other. This is the from regions of high concentration to regions of low underlying principle of dosage form design. concentration. Lipid solubility and the degree of ionization of the drug at the absorbing site influence Biopharmaceutical aspects the rate of diffusion. Recent research into carrier- mediated transport mechanisms has provided much of dosage form design information and knowledge, providing guidance in some cases for the design of new drug molecules. Biopharmaceutics can be regarded as the study of Several specialized transport mechanisms are postu- the relationship between the physical, chemical and lated, including active and facilitated transport. Once biological sciences applied to drugs, dosage forms absorbed, the drug can exert a therapeutic effect and drug action. Clearly, understanding the principles either locally or at a site of action remote from the of this subject is important in dosage form design, site of administration. In the latter case the drug has particularly with regard to drug absorption, as well to be transported in body fluids (Fig. 1.1). Gastrointestinal Skin tract Oral Buccal Topical Vascular Mouth system preparations Subcutaneous injection Direct Intramuscular injection Vascular system or Stomach hepato- Circulatory enteric system Respiratory Small (drug or tract intestine metabolites) Vascular Aerosols system Large Gases intestine Intravenous injection Rectal Rectal Rectum preparations Drug or metabolite in tissues, extracellular Copyright © 2017. Elsevier. All rights reserved. Drug in fluids and faeces Kidneys lymphatics Drug or metabolites Drug or metabolites in in urine saliva, exhaled air, etc. Excretion Elimination Fig. 1.1 Pathways a drug may take following the administration of a dosage form by different routes. 8 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  Design of dosage forms CHAPTER 1 When the dosage form is designed to deliver drugs since they will be dealt with in greater detail later via the buccal, respiratory, rectal, intramuscular or in this book. subcutaneous routes, the drug passes directly into the circulating blood from absorbing tissues, whilst the intravenous route provides the most direct route Oral route of all. When a drug is delivered by the oral route, The oral route is the most frequently used route for onset of drug action will be delayed because of drug administration. Oral dosage forms are intended the required transit time in the gastrointestinal usually for systemic effects resulting from drug tract before absorption, the absorption process and absorption through the various epithelia and mucosa factors associated with hepatoenteric blood circula- of the gastrointestinal tract. A few drugs, however, tion. The physical form of the oral dosage form will are intended to dissolve in the mouth for rapid also influence the absorption rate and onset of action, absorption or for local effect in the gastrointestinal with solutions acting faster than suspensions, which tract because of poor absorption by this route or low in turn generally act faster than capsules and tablets. aqueous solubility. Compared with other routes, the Dosage forms can thus be listed in order of the time oral route is the simplest, most convenient and safest of onset of the therapeutic effect (Table 1.2). means of drug administration. However, disadvantages However, all drugs irrespective of their delivery route include the relatively slow onset of action and pos- remain foreign to the human body, and distribution, sibilities of irregular absorption and destruction of metabolic and elimination processes commence certain drugs by the enzymes and secretions of the immediately following drug absorption until the gastrointestinal tract. For example, insulin-containing drug is eliminated from the body via the urine, preparations are inactivated by the action of stomach faeces, saliva, skin or lungs in unchanged or metabo- fluids. lized form. Whilst drug absorption from the gastrointestinal tract follows the general principles described later in this book, several specific features should be Routes of drug administration emphasized. Changes in drug solubility can result from reactions with other materials present in the The absorption pattern of drugs differs considerably gastrointestinal tract; for example, interference with between individual drug substances, as well as between absorption of tetracyclines through the formation of the different administration routes. Dosage forms insoluble complexes with calcium, which can be are designed to provide the drug in a suitable form available from foodstuffs or formulation additives. for absorption from each selected route of administra- Gastric emptying time is an important factor for tion. The following discussion considers briefly the effective drug absorption from the intestine. Slow routes of drug administration and, whilst dosage forms gastric emptying can be detrimental to drugs inacti- are mentioned, this is intended only as an introduction vated by the gastric juices and can delay absorption of drugs more effectively absorbed from the intestine. In addition, since environmental pH can influence Table 1.2 Variation in time of onset of action for the ionization and lipid solubility of drugs, the pH different dosage forms change occurring along the gastrointestinal tract, from Time of onset Dosage forms a pH as low as 1 in the stomach to approximately 7 of action or 8 in the large intestine, is important for both the degree and the site of drug absorption. Since mem- Copyright © 2017. Elsevier. All rights reserved. Seconds Intravenous injections branes are more permeable to un-ionized forms than Minutes Intramuscular and subcutaneous to ionized forms and since most drugs are weak acids injections, buccal tablets, aerosols, gases or bases, it can be shown that weak acids, being Minutes to Short-term depot injections, solutions, largely un-ionized, are well absorbed from the hours suspensions, powders, granules, stomach. In the small intestine (pH from approxi- capsules, tablets, modified-release tablets mately 4 to 6.5), with its extremely large absorbing Several hours Gastro-resistant coated formulations surface, both weak acids and weak bases are well Days to weeks Depot injections, implants absorbed. The most popular oral dosage forms are tablets, Varied Topical preparations capsules, suspensions, solutions and emulsions. Tablets 9 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  CHAPTER 1  are prepared by compaction and contain drugs and than solid dosage forms or suspensions since drug formulation additives which are included for specific dissolution is not required. functions, such as disintegrants, which promote tablet break-up into granules and powder particles in the gastrointestinal tract, facilitating drug dissolution and Rectal route absorption. Tablets are often coated, either to provide Drugs given rectally in solution, suppository or emul- a protective barrier to environmental factors for drug sion form are generally administered for local rather stability purposes or to mask unpleasant drug taste, than systemic effects. Suppositories are solid forms as well as to protect drugs from the acid conditions intended for introduction into body cavities (usually of the stomach (gastro-resistant coating). Increasing rectal but also vaginal and urethral), where they melt, use is being made of modified-release tablet products releasing the drug. The choice of suppository base such as fast-dissolving systems and controlled-release, or drug carrier can greatly influence the degree and delayed-release or sustained-release formulations. The rate of drug release. This route of drug administration benefits of controlled-release tablet formulations, is also indicated for drugs inactivated by the achieved, for example, by the use of polymeric-based gastrointestinal fluids when given orally or when the tablet cores or coating membranes, include reduced oral route is precluded, for example when a patient frequency of drug-related side effects and maintenance is vomiting or unconscious. Drugs administered of steady levels of drug in the plasma for extended rectally enter the systemic circulation without passing periods, which are important when medications are through the liver, an advantage for drugs significantly delivered for chronic conditions or where constant inactivated by the liver following oral route absorption. levels are required to achieve optimal efficacy, as in Disadvantageously, the rectal route is inconvenient treatment of angina and hypertension. and drug absorption is often irregular and difficult Capsules are solid dosage forms containing the to predict. drug and, usually, appropriate filler(s), enclosed in a hard or soft shell composed primarily of gelatin or other suitable polymeric material. As with tablets, Parenteral routes uniformity of dose can be readily achieved, and A drug administered parenterally is one injected via various sizes, shapes and colours of the shell are a hollow needle into the body at various sites and to commercially available. The capsule shell readily various depths. The three main parenteral routes are ruptures and dissolves following oral administration, subcutaneous, intramuscular and intravenous. Other and in most cases drugs are released from capsules routes, such as intracardiac and intrathecal, are used faster than from tablets. Recently, increased interest less frequently. The parenteral route is preferred when has been shown in the filling of hard capsules with rapid absorption is essential, as in emergency situations semisolid and microemulsion formulations to provide or when patients are unconscious or unable to accept rapidly dispersing dosage forms for poorly soluble oral medication, and in cases when drugs are drugs. destroyed, inactivated or poorly absorbed following Suspensions, which contain finely divided drugs oral administration. In general, the blood levels suspended in a suitable vehicle, are a useful means attained are more predictable than those achieved of administering large amounts of drugs that would by oral dosage forms. be inconvenient if they were taken in tablet or capsule Injectable preparations are usually sterile solutions form. They are also useful for patients who experience or suspensions of drugs in water or other suitable difficulty in swallowing tablets and capsules and physiologically acceptable vehicles. As referred to Copyright © 2017. Elsevier. All rights reserved. for paediatric use. Whilst dissolution of drugs is previously, drugs in solution are rapidly absorbed, required before absorption, the fine solid particles and thus suspension injections act more slowly than in a suspension have a large surface area to present solution injections. In addition, since body to the gastrointestinal fluids, and this facilitates drug fluids are aqueous, by use of drugs suspended in oily dissolution, thus aiding absorption and thereby the vehicles, a preparation exhibiting slower absorption onset of drug action. Not all oral suspensions, however, characteristics can be formulated to give a depot are formulated for systemic effects, and several are preparation, providing a reservoir of the drug, which designed for local effects in the gastrointestinal tract. is released slowly into the systemic circulation. Such On the other hand, solutions, including formulations preparations are administered by intramuscular such as syrups and linctuses, are absorbed more rapidly injection deep into skeletal muscles (e.g. several 10 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  Design of dosage forms CHAPTER 1 penicillin-containing injections). Alternatively, depot determining the character of drug release from the preparations can be achieved by subcutaneous implants formulation. Ointments are hydrophobic, oleaginous- or pellets, which are compacted or moulded discs based dosage forms, whereas creams are semisolid of drug placed in loose subcutaneous tissue under emulsions. Pastes contain more solids than ointments the outer layers of the skin. Such systems include and thus are stiffer. For topical application in liquid solid microspheres and biodegradable polymeric form other than solution, lotions, suspensions of solids microspheres (e.g. lactide and glycolic acid homopoly- in aqueous solution or emulsions are used. mers and copolymers) containing proteins or peptides Application of drugs to other topical surfaces such (e.g. human growth hormone and leuprolide). More as the eye, ear and nose is common, and ointments, generally, subcutaneous injections are aqueous solutions creams, suspensions and solutions are used. Oph- or suspensions which allow the drug to be placed in thalmic preparations are required, amongst other the immediate vicinity of blood capillaries. The drug features, to be sterile. Nasal dosage forms include then diffuses into the capillaries. Inclusion of vaso- solutions or suspensions delivered by drops or fine constrictors or vasodilators in subcutaneous injections aerosol from a spray. Ear formulations, in general, will clearly influence blood flow through the capillaries, are viscous to prolong contact with affected areas. thereby modifying the capacity for absorption. This principle is often used in the administration of local Respiratory route anaesthetics with the vasoconstrictor adrenaline, which delays drug absorption. Conversely, increased drug The lungs provide an excellent surface for absorption absorption can result when vasodilators are included. when the drug is delivered in gaseous, aerosol mist Intravenous administration involves injection of sterile or ultrafine solid particle form. For drug particles aqueous solutions directly into a vein at an appropriate presented to the lungs as an aerosol, particle size rate. The volumes delivered can range from a few largely determines the extent to which they penetrate millilitres, as in emergency treatment or for hypnotics, the alveolar region, the zone of rapid absorption. to litre quantities, as in replacement fluid treatment Drug particles that have diameters in the region of or parenteral nutrition. 1 µm to 5 µm reach the deep lung. Particles smaller Given the generally negative patient acceptance than 1 µm are largely exhaled, and particles larger of this important route of drug delivery, primarily than 5 µm are deposited on larger bronchial airways. associated with pain and inconvenience, recent This delivery route is particularly useful for the direct developments to help with self-injection by patients treatment of asthma, with use of both powder aerosols have focused on ‘needle-free’ injection systems and (e.g. salmeterol xinafoate) and pressurized metered- devices which propel the drug in aqueous solution dose inhalers containing the drug in liquefied inert or powder form at high velocity directly through the propellant (e.g. salbutamol sulfate inhaler). Impor- external layers of the skin. tantly, this delivery route is being increasingly rec- ognized as a useful means of administering the therapeutic agents emerging from biotechnology Topical route requiring systemic distribution and targeted delivery, Drugs are applied topically (i.e. to the skin) mainly such as peptides and proteins. for local action. Whilst this route can also be used for systemic drug delivery, percutaneous absorp- tion is often poor and erratic, although several Drug factors in dosage transdermal patches delivering drugs for systemic form design Copyright © 2017. Elsevier. All rights reserved. distribution (e.g. fentanyl patches for severe pain management and nicotine patches for cessation of Each type of dosage form requires careful study smoking) are available. The drugs applied to the skin of the physical and chemical properties of drug for local effect include antiseptics, antifungals and substances to achieve a stable, efficacious product. anti-inflammatory agents, as well as skin emollients These properties, such as dissolution, crystal size and for protective effects. polymorphic form, solid-state stability and drug– Pharmaceutical topical formulations – ointments, additive interaction, can have profound effects on creams and pastes – are composed of the drug in a the physiological availability and physical and chemical suitable semisolid base which is either hydrophobic stability of the drug. Through combination of or hydrophilic. The bases play an important role in such information and knowledge with that from 11 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  CHAPTER 1  pharmacological and biochemical studies, the most of powders. Drug dissolution rate, drug absorption suitable drug form and additives can be selected for rate, drug content uniformity in dosage forms and the formulation of chosen dosage forms. stability are all dependent to various degrees on Whilst comprehensive property evaluation will not particle size, particle size distribution and particle be required for all types of formulations, those interaction with solid surfaces. In many cases, for properties which are recognized as important in dosage both drugs and additives, particle size reduction is form design and processing are listed in Table 1.3. required to achieve the desired physicochemical The stresses to which the formulation might be characteristics. exposed during processing and manipulation into It is now generally recognized that poorly water- dosage forms, as well as the procedures involved are soluble drugs showing a dissolution-rate-limiting step also listed in Table 1.3. Variations in physicochemical in the absorption process will be more readily bioavail- properties, occurring, for example, between batches able when administered in a finely subdivided form of the same material or resulting from alternative with a larger surface than as a coarse material. Examples treatment procedures, can modify the formulation include griseofulvin, tolbutamide, indometacin and requirements, as well as processing and dosage form nifedipine. The fine material, often of micrometre performance. For instance, the fine milling of poorly or nanometre size, with large specific surface area, water-soluble drug substances can modify their dissolves at a faster rate, which can lead to increased wetting and dissolution characteristics, important drug absorption by passive diffusion. With many of properties during granulation and product performance the new drugs being introduced exhibiting extremely respectively. Careful evaluation of these properties low aqueous solubility, alternative formulation and understanding of the effects of these stresses on strategies to enhance drug dissolution are being used, these parameters are therefore important in dosage such as coprecipitates of drug and adjuvant particles, form design and processing, as well as for product complexation with hydrophilic polymers or oligosac- performance. charides, or the formation of co-crystals with hydrophilic templating compounds. The rate of drug dissolution can be adversely Particle size and surface area affected, however, by unsuitable choice of formulation additives, even though solids of appropriate particle Particle size reduction results in an increase in the size are used. Tableting lubricant powders, for specific surface area (i.e. surface area per unit weight) example, can impart hydrophobicity to a formulation and inhibit drug dissolution. Fine powders can also increase air adsorption or static charge, leading to Table 1.3 Properties of drug substances important in wetting or agglomeration problems. Micronizing drug dosage form design and potential stresses occurring powders can lead to changes in crystallinity and during processes, with a range of manufacturing particle surface energy which cause reduced chemical procedures stability. Drug particle size also influences content Properties Processing Manufacturing uniformity in solid dosage forms, particularly for stresses procedures low-dose formulations. It is important in such cases Particle size, Pressure Precipitation to have as many particles as possible per dose to surface area Mechanical Filtration minimize potency variation between dosage units. Particle surface Radiation Emulsification Other dosage forms are also affected by particle size, chemistry Exposure to Milling including suspensions (for controlling flow properties Copyright © 2017. Elsevier. All rights reserved. Solubility liquids Mixing and particle interactions), inhalation aerosols (for Dissolution Exposure to gases Drying optimal penetration of drug particles to absorbing Partition and liquid vapours Granulation mucosa) and topical formulations (for freedom from coefficient Temperature Compaction grittiness). Ionization constant Autoclaving Crystal properties, Crystallization polymorphism Handling Solubility Stability Storage Organoleptic Transport All drugs, regardless of their administration route, Molecular weight must exhibit at least limited aqueous solubility for 12 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  Design of dosage forms CHAPTER 1 therapeutic efficacy. Thus, relatively insoluble com- The dissolution of a drug is described in a simplified pounds can exhibit erratic or incomplete absorption, manner by the Noyes–Whitney equation: and it might be appropriate to use a more soluble salt or other chemical derivatives. Alternatively, micronizing, dm = kA(Cs − C ) complexation or solid dispersion techniques might be dt used. Solubility, and especially the degree of saturation (1.1) in the vehicle, can also be important in the absorption of drugs already in solution in liquid dosage forms, where dm/dt is the dissolution rate, k is the dissolution since precipitation in the gastrointestinal tract can rate constant, A is the surface area of dissolving solid, occur, modifying bioavailability. Cs is the drug’s solubility and C is the concentration The solubilities of acidic or basic compounds are of the drug in the dissolution medium at time t. The pH dependent and can be altered by their forming equation reveals that the dissolution rate can be raised salts, with different salts exhibiting different equi- by increase of the surface area (reducing particle size) librium solubilities. However, the solubility of a salt of the drug, by increase of the solubility of the drug in of a strong acid is less affected by changes in pH the diffusion layer and by increase of k, which in this than the solubility of a salt of a weak acid. In the equation incorporates the drug diffusion coefficient latter case, when the pH is lower, the salt hydrolyses and the diffusion layer thickness. During the early to an extent dependent on the pH and pKa, resulting phases of dissolution, Cs > C, and if the surface area, in decreased solubility. Reduced solubility can also A, and experimental conditions are kept constant, occur for slightly soluble salts of drugs through the then k can be determined for compacts containing common-ion effect. If one of the ions involved is drug alone. The constant k is termed the intrinsic added as a different, more soluble salt, the solubility dissolution rate constant and is a characteristic of product can be exceeded and a portion of the drug each solid drug compound in a given solvent under precipitates. fixed hydrodynamic conditions. Drugs with values of k less than 0.1 mg cm−2 usually exhibit dissolution-rate-limited absorption. Dissolution This value is a helpful guide figure indicating the level below which drug dissolution becomes the As mentioned already, for a drug to be absorbed it rate-limiting step in absorption. Particulate dissolution must first be dissolved in the fluid at the site of can also be examined where an effort is made to absorption. For example, an orally administered drug control A, and formulation effects can be studied. in tablet form is not absorbed until drug particles Dissolution rate data, when combined with solubil- are dissolved or solubilized by the fluids at some ity, partition coefficient and pKa data, provide an point along the gastrointestinal tract, depending on insight into the potential in vivo absorption charac- the pH–solubility profile of the drug substance. teristics of a drug. However, in vitro tests have sig- Dissolution describes the process by which the drug nificance only when they are related to in vivo results. particles dissolve. Once such a relationship has been established, in During dissolution, the drug molecules in the vitro dissolution tests can be used as a predictor of surface layer dissolve, leading to a saturated solution in vivo behaviour. The importance of dissolution around the particles to form the diffusion layer. testing, for quality control purposes, has been widely Dissolved drug molecules then pass throughout the recognized by official compendia, as well as drug dissolving fluid to contact absorbing mucosa and are regulatory authorities, with the inclusion of dissolution Copyright © 2017. Elsevier. All rights reserved. absorbed. Replenishment of diffusing drug molecules specifications using standardized testing procedures in the diffusion layer is achieved by further drug for a range of preparations. dissolution, and the absorption process continues. If The Biopharmaceutics Classification System (BCS), dissolution is fast or the drug remains in solution established in 1995, is a guide for predicting the form, the rate of absorption is primarily dependent intestinal absorption of drugs for orally administered on the ability of the drug to traverse the absorbing medicines on the basis of the solubility, dissolu- membrane. If, however, drug dissolution is slow tion ability, and permeation ability of drugs. This because of its physicochemical properties or formula- system has proved extremely useful in aiding the tion factors, then dissolution may be the rate-limiting design of oral medicines and has recently been step in absorption and impacts drug bioavailability. extended with the Biopharmaceutics Drug Disposition 13 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  CHAPTER 1  Classification System (BDDCS) to incorporate dosage forms. However, for those substances com- drug absorption and transport, and the effects of posed of or containing powders or compacted powders metabolism. in the finished product, the crystal properties and solid-state form of the drug must be carefully con- sidered. It is well recognized that drug substances Partition coefficient and pKa can be amorphous (i.e. without regular molecular lattice arrangements), crystalline, anhydrous, in various As pointed out earlier, for relatively insoluble com- degrees of hydration or solvated with other entrapped pounds the dissolution rate is often the rate- solvent molecules, as well as differing in crystal determining step in the overall absorption process. hardness, shape and size. In addition, many drug Alternatively, for soluble compounds the rate of substances can exist in more than one form with permeation across biological membranes is the rate- different molecular packing arrangements in the determining step. Whilst the dissolution rate can be crystal lattice. This property is termed polymorphism, changed by modification of the physicochemical and different polymorphs may be prepared by properties of the drug and/or alteration of the for- manipulation of the conditions of particle formation mulation composition, the permeation rate is depend- during crystallization, such as solvent, temperature ent on the size, relative aqueous and lipid solubilities and rate of cooling. It is known that only one form and ionic charge of drug molecules, factors which of a pure drug substance is stable at a given tem- can be altered through molecular modifications. The perature and pressure, with the other forms, termed absorbing membrane acts as a lipophilic barrier to metastable, converting at different rates to the stable the passage of drugs, which is related to the lipophilic crystalline form. The different polymorphs differ in nature of the drug molecule. The partition coefficient, their physical properties such as dissolution ability for example between oil and water, is a measure of and solid-state stability, as well as processing behaviour lipophilic character. in terms of powder flow and compaction during Most low molecular weight drugs are weak acids tableting in some cases. or bases and, depending on the pH, exist in an ionized These different crystalline forms can be of con- or un-ionized form. Membranes of absorbing mucosa siderable importance in relation to the ease or dif- are more permeable to un-ionized forms of drugs ficulty of formulation and as regards stability and than to ionized species because of the greater lipid biological activity. As might be expected, higher solubility of the un-ionized forms and the highly dissolution rates are obtained for metastable poly- charged nature of the cell membrane, which results morphic forms; for example, the alternative poly- in the binding or repelling of the ionized drug, thereby morphic forms of rifaximin exhibit different in vitro decreasing penetration. dissolution rates and bioavailability. In some cases, The dominating factors that therefore influence amorphous forms are more active than crystalline the absorption of weak acids and bases are the pH forms. at the site of absorption and the lipid solubility The polypeptide hormone insulin, widely used in of the un-ionized species. These factors, together with the regulation of carbohydrate, fat and protein the Henderson–Hasselbalch equations for calculating metabolism, also demonstrates how differing degrees the proportions of ionized and un-ionized species at of activity can result from the use of different crystal- a particular pH, constitute the pH-partition theory line forms of the same agent. In the presence of for drug absorption. However, these factors do not acetate buffer, zinc combines with insulin to form describe completely the process of absorption as an extremely insoluble complex of the proteinaceous Copyright © 2017. Elsevier. All rights reserved. certain compounds with low partition coefficients hormone. This complex is an amorphous precipitate and/or which are highly ionized over the entire or crystalline product depending on the environmental physiological pH range show good bioavailability, and pH. The amorphous form, containing particles of therefore other factors are clearly involved. no uniform shape and smaller than 2 µm, is absorbed following intramuscular or subcutaneous injection and has a short duration of action, whilst Crystal properties: polymorphism the crystalline product, consisting of rhombohedral crystals of size 10 µm to 40 µm, is more slowly Practically all drug substances are handled in powder absorbed and has a longer duration of action. Insulin form at some stage during their manufacture into preparations which are intermediate in duration of 14 Aulton's Pharmaceutics E-Book : Aulton's Pharmaceutics E-Book, edited by Kevin M. G. Taylor, and Michael E. Aulton, Elsevier, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/trinitycollege/detail.action?docID=5253018. Created from trinitycollege on 2025-01-27 11:34:34.  Design of dosage forms CHAPTER 1 action are prepared by use of physical mixtures of Whilst the mechanisms of solid-state degradation are these two products. complex and often difficult to analyse, a full under- Polymorphic transitions can also occur during standing is not a prerequisite in the design of a suitable milling, granulating, drying and compacting opera- formulation containing solids. For example, in cases tions (e.g. transitions during milling for digoxin and where drug substances are sensitive to hydrolysis, spironolactone). Granulation can result in solvate steps such as minimization of exposure to moisture formation, and during drying, a solvent or water during preparation, low moisture content specifications molecule(s) may be lost to form an anhydrous for the final product and moisture-resistant packaging material. Consequently, the formulator must be can be used. For oxygen-sensitive drugs, antioxidants aware of these potential transformations which can can be included in the formulation and, as with result in undesirable modified product performance, light-sensitive materials, suitable packaging can reduce even though routine chemical analyses may not or eliminate the problem. For drugs administered in reveal any changes. Reversion from metastable liquid form, the stability in solution, as well as the forms, if used, to the stable form may also occur effects of pH over the physiological range of pH 1–8, during the lifetime of the product. In suspen- should be understood. Buffers may be required to sions, this may be accompanied by changes in the control the pH of the preparation to increase stability; consistency of the preparation, which affects its where liquid dosage forms are sensitive to microbial shelf life and stability. Such changes can often be