1 The design of dosage forms Peter York CHAPTER CONTENTS Principles of dosage form design 1 Biopharmaceutical aspects of dosage. Pharmaceutics: the science of dosage form design subject in the pharmacy curriculum, encompassing design of drugs, their manufacture, and Format: PDF. Aulton__PharmaceuticsThe Science of Dosage Form Design 2 Ed - Free ebook download as PDF File .pdf), Text File .txt) or read book online for free. hhhhh.

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Aulton's Pharmaceutics: The Science of Dosage Form Design Here is the link. Get this from a library! Pharmaceutics: the science of dosage form design. [ Michael E Aulton;] -- A comprehensive textbook covering the design of dosage forms. PHARMACEUTICS: THE SCIENCE OF DOSAGE FORM DESIGN, LONDON: CHURCHILL LIVINGSTONE, GB,. PAGE(S) - , ISBN: .

Sudan the widely used tableting lubricant magnesium IV or insoluble in both e. Lakes in formulations containing this drug. However, in recent years the inclu- Unfortunately, many drug substances in use today sion of colours in formulations has become are unpalatable and unattractive in their natural state extremely complex because of the banning of many and dosage forms containing such drugs, particu- traditionally used colours in many countries.

The Extra Pharmacopoeia. The use of flavours applies primarily to liquid dosage forms intended for oral administration. Available as concentrated extracts, solutions, Other drug properties adsorbed on to powders or microencapsulated, At the same time as ensuring that dosage forms are flavours are usually composed of mixtures of natural chemically and physically stable and are therapeuti- and synthetic materials. The taste buds of the cally efficacious, it is also relevant to establish that tongue respond quickly to bitter, sweet, salt or acid the selected formulation is capable of efficient and, elements of a flavour.

In addition, unpleasant taste in most cases, large-scale manufacture. In addition can be overcome by using water-insoluble deriva- to those properties previously discussed, such as par- tives of drugs which have little or no taste.

An ticle size and crystal form, other characteristics, such example is the use of amitriptyline pamoate. In such as hygroscopicity, flowability and compressibility, are approaches other factors, such as bioavailability, particularly valuable when preparing solid dosage must remain unchanged. If an insoluble derivative is forms where the drugs constitute a large percentage unavailable or cannot be used, a flavour or perfume of the formulation. Hygroscopic drugs can require can be used. Alternatively, unpleasant drugs can be low-moisture manufacturing environments and need administered in capsules or prepared as coated par- to avoid water during preparation.

Poorly flowing. In addition to local effects, systemic effects Attwood, D. Topical preparations are Florence, A. Principles of Pharmacy, 3rd Edn. Palgrave, London. Therapeutic aerosols are discussed in more detail in Rosen, M. John Wiley and Sons, New York.

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Shaw, D. Butterworth-Heinemann, Oxford. Studies of the compressibility of their convenience. However, alternative liquid prepa- drug substances are frequently undertaken using rations are usually available for those unable to take instrumented tablet machines in formulation labora- tablets and capsules.

Alternative technologies for preparing particles with required properties - crystal engineering - provide new opportunities. Undoubtedly these new technologies The nature of the clinical indication, disease or and others, as well as sophisticated formulations, will illness against which the drug is intended is an be required to deal with peptide and protein drugs, important factor when selecting the range of dosage the advent of gene therapy and the need to deliver forms to be prepared.

Factors such as the need for such labile macromolecules to specific cells in the systemic or local therapy, the duration of action body. Interest is also likely to be directed to individ- required and whether the drug will be used in emer- ual patient requirements, such as age, weight and gency situations, need to be considered. In the vast physiological and metabolic factors, features that can majority of cases a single drug substance is prepared influence drug absorption and bioavailability.

For example, many asthmatic patients use inhalation SUMMARY aerosols from which the drug is rapidly absorbed into the systematic circulation following deep inhala- This chapter has demonstrated that the formulation tion for rapid emergency relief, and oral products for of drugs into dosage forms requires the interpreta- chronic therapy.

Although the physical and toris, a coronary circulatory problem, place tablets of chemical properties of drugs and additives need to nitroglycerin sublingually for rapid drug absorption be understood, the factors influencing drug absorp- from the buccal cavity.

Thus, although systemic tion and the requirements of the disease to be effects are generally obtained following oral and par- treated also have to be taken into account when enteral drug administration, other routes can be identifying potential delivery routes. The formula- employed as the drug and the situation demand. Some drugs may be well mation by pharmaceutical scientists to achieve the absorbed by one route and not another, and must objective of creating high-quality and efficacious therefore be considered individually.

The age of the patient also plays a role in defining the types of dosage forms made available.

Pharmaceutics : the science of dosage form design

Infants generally prefer liquid dosage forms, usually solu- tions and mixtures, given orally. A theoretical basis for a biopharmaceutical drug classification: Children can have dissolution and bioavailability.

Pharmaceutical Research, 12, difficulty in swallowing solid dosage forms, and for Modern Pharmaceutics, 3rd edn.

Rhodes, C. Marcel Dekker. Physical Pharmacy: Pharmaceutical Sciences, 4th edn. Lea and Febiger, Philadelphia. Pfeiffer, R. Definition of terms 16 Factors affecting the solubility of solids in Solution, solubility 16 liquids 25 Expressions of concentration 16 Temperature 25 Quantity per quantity 16 Molecular structure of solute 26 Percentage 16 Nature of solvent: Solutions are encountered extremely frequently in ity of a substance is the amount of it that passes into pharmaceutical development, either as a dosage solution when equilibrium is established between form in their own right or as a clinical trials mater- the solution and excess undissolved substance.

The ial. Equally importantly, almost all drugs function in solution that is obtained under these conditions is solution in the body. This book therefore starts with said to be saturated. It will discuss this process par- solution are either both gases or both liquids it is ticularly in the context of a solid dissolving in a more usual to talk in terms of miscibility rather liquid, as this is the situation most likely to be than solubility.

The student is therefore Expressions of concentration encouraged to refer to the bibliography at the end of each chapter in order to augment the present con- Quantity per quantity tents. The textbook written by Florence and Attwood Concentrations are often expressed simply as the is particularly recommended because of the weight or volume of solute that is contained in a large number of pharmaceutical examples that are given weight or volume of the solution.

The majority used to aid an understanding of physicochemical of solutions encountered in pharmaceutical practice principles.

Consequently, concentration is expressed most commonly by the weight of solute contained in a given volume of solu- tion. For example, in This chapter begins by clarifying a number of terms the case of a solution with a concentration of 1 kg relevant to the formation and concentration of solu- m 3 the strength may be denoted by any one of the tions following concentration terms, depending on the circumstances: Solution, solubility 1 g L -1, 0.

The com- Percentage ponent that determines the phase of the solution is termed the solvent and usually constitutes the Pharmaceutical scientists have a preference for largest proportion of the system. The other compo- quoting concentrations in percentages. The concen- nents are termed solutes, and these are dispersed as tration of a solution of a solid in a liquid is given by: Thus, the solubil- tions of gases in liquids.

In the case of electrolytes, however, volume of solution, then changes in volume caused by these concentrations may still be expressed in terms temperature fluctuations will alter the concentration.

A milliequivalent mEq of an ion is, in fact, one thousandth of the gram equivalent of the ion, which is in turn the ionic Parts weight expressed in grams divided by the valency of Pharmacopoeias express some concentrations in the ion. Alternatively, terms of the number of 'parts' of solute dissolved in a stated number of 'parts' of solution. The use of this method to describe the strength of a solution of a solid in a liquid implies that a given number of parts A knowledge of the concept of chemical equivalents by volume mL of solution contain a certain number is also required in order to understand the use of of parts by weight g of solid.

In the case of solutions 'normality' as a means of expressing the concentra- of liquids in liquids, parts by volume of solute in parts tion of solutions, because a normal solution, i. It was thought that this term would disap- pear on the introduction of SI units, but it is still encountered in some volumetric assay procedures. Molarity This is the number of moles of solute contained in 1 dm3 or, more commonly in pharmaceutical science, 1 litre of solution.

The unit of molarity is mol L'1 equivalent to mol m3 if con- States of matter verted to the strict SI unit. The kinetic theory of matter indicates that in con- densed phases the thermal motions of molecules are Molality reduced sufficiently so that intermolecular forces of attraction result in the formation of coherent masses This is the number of moles of solute divided by the of molecules, unlike the situation in gaseous phases, mass of the solvent, i.

In solid condensed phases maceutical science than the other terms it does offer the thermal motion of molecules or ions is virtually a more precise description of concentration because restricted to vibrations about mean positions and the it is unaffected by temperature. This is often used in theoretical considerations and is In liquid condensed systems the thermal motions of defined as the number of moles of solute divided by molecules are greater than those in solids but less the total number of moles of solute and solvent, i.

The structure of liquids is there- fore intermediate between that of solids and that of mole fraction of solute x gases. The process of dissolution may therefore be consid- resulting from the removal of a solute molecule from ered to involve the relocation of a solute molecule its original environment plus that resulting from its from an environment where it is surrounded by other new location in the solvent. For example, in the case identical molecules, with which it forms intermolecu- of a crystalline solid dissolving in a liquid these con- lar attractions, into a cavity in a liquid, where it is sur- tributions can be described by Eqn 2.

Its value AHci is always positive and Affsolv is most com- decreases during a spontaneously occurring process monly negative. In these cases heat is more energy can be made available, i. In some This change in free energy is defined by the gen- systems, where marked affinity between solute and erally applicable thermodynamic equation: The overall enthalpy change then becomes negative, so that heat is where AH, which is known as the change in the evolved and the process is an exothermic one.

Dissolution mechanisms The entropy change AS is usually positive for any process, such as dissolution, that involves mixing The dissolution of a solid in a liquid may be of two or more components. In an ideal solution regarded as being composed of two consecutive there is, by definition, no net change in the inter- stages.

First is an interfacial reaction that results in the solvent when dissolution occurs. In such circum- liberation of solute molecules from the solid stances AH - 0. Thus, the free energy change AG phase. This involves a phase change, so that during the formation of an ideal solution is dictated molecules of solid become molecules of solute in solely by the term TAS. The In most real systems dissolution is accompanied solution in contact with the solid will be by a change in the intermolecular forces experienced saturated because it is in direct contact with by the solute and the solvent before and after the undissolved solid.

Its concentration will be Cs, a event. A change in enthalpy will therefore accom- saturated solution. Equation 2. After this, the solute molecules must migrate cates that the likelihood of dissolution will depend through the boundary layers surrounding the on the sign of AH and, if this sign is positive, on the crystal to the bulk of the solution, at which time value of AH relative to that of.

In other words, its concentration will be C. This step involves the it follows from Eqn 2. Boundary layers are static or slow- The overall change in enthalpy of dissolution AH moving layers of liquid that surround all wetted can be regarded as being made up of the change solid surfaces see Chapter 4 for further details.

Mass transfer takes place more slowly through the bulk of the solution C2. If the concentration of the bulk C2 is greater The concentration of the solution in the than this, the solution is referred to as supersatu- boundary layers changes therefore from being rated and the movement of solid molecules will be in saturated Cs at the crystal surface to being the direction of bulk to surface as during crystal- equal to that of the bulk of the solution C at its lization , and if C2 is less than saturated the mole- outermost limit.

These stages are illustrated in Figure 2. An equation known as the Noyes-Whitney equa- Like any reaction that involves consecutive stages, tion was developed to define the dissolution from a the overall rate of dissolution will depend on single spherical particle.

The rate of mass transfer whichever of these steps is the slowest the rate- of solute molecules or ions through a static diffu- determining or rate-limiting step. This relation- liquid that exists at a solid-liquid interface. If the solute is removed from the dissolution medium by some process at a faster rate than it where the constant k is the rate constant s"1.

In either of these circumstances dissolution is said to occur under 'sink' conditions, and Eqn 2.

It should be realised that such 'sink' conditions may arise in vivo when a drug is absorbed from its solu- tion in the gastrointestinal fluids at a faster rate than it dissolves in those fluids from a solid dosage form such as a tablet. If solute is allowed to accumulate in the dissolu- tion medium to such an extent that the above approximation is no longer valid, i. One such drug is the glucocorticoid pred- is often necessary to carefully select the most appro- nisolone, used in the suppression of inflammatory and priate chemical form of the drug.

For example, such allergic disorders. Through the use of different chem- selection should address solubility requirements, ical forms and formulation additives a range of effec- drug particle size and physical form, and consider tive anti-inflammatory preparations are available, appropriate additives and manufacturing aids including tablet, enteric-coated tablet, injections, eye coupled to selecting the most appropriate adminis- drops and enema.

The extremely low aqueous solubil- tration route s and dosage form s. Suitable manu- ity of the base prednisolone and acetate salt makes facturing processes and packaging are also required.

Pharmaceutics: solid dosage form design, biomaterials and particulate technology

Dosage form, and solutions for eye and ear drops, enema and forms can be designed for administration by alterna- intravenous injection to be prepared. The analgesic tive delivery routes to maximize therapeutic paracetamol is also available in a range of dosage response. Preparations can be taken orally or forms and strengths to meet specific needs of the user, injected, as well as being applied to the skin or including tablets, dispersible tablets, paediatric inhaled, and Table 1. However, it is necessary to pension and suppositories.

These can be illness often requires a specific type of drug therapy. In addition, factors governing the choice of adminis- 1. Biopharmaceutical considerations, including tration route and the specific requirements of that factors affecting the absorption of the drug route which affect drug absorption need to be taken substance from different administration routes; into account when designing dosage forms.

Drug factors, such as the physical and chemical Many drugs are formulated into several dosage properties of the drug substance; forms of varying strengths, each having selected phar- 3. Therapeutic considerations, including consideration of the clinical indication to be treated and patient factors.

This is the Oral Solutions, syrups, suspensions, underlying principle of dosage form design. Clearly, understanding the principles of emulsion, powder forms this subject is important in dosage form design, par- inhalations, sprays, gases ticularly with regard to drug absorption, as well as Nasal Solutions, inhalations drug distribution, metabolism and excretion.

In Eye Solutions, ointments, creams general, a drug substance must be in solution form Ear Solutions, suspensions, ointments before it can be absorbed via the absorbing mem- creams branes and epithelia of the skin, gastrointestinal tract and lungs into body fluids. Drugs are absorbed in two. Summary of factors affecting dissolution tion factors on the rates of release of drugs into solu- rates tion from various dosage forms.

These factors may be derived from a consideration of the terms that appear in the Noyes-Whitney equa- tion Eqn 2. Most of the effects of these Because the rate of dissolution is dependent on so factors are included in the summary given in Table many factors, it is advantageous to have a measure of 2.

It should be borne in mind that pharmacists are the rate of dissolution which is independent of rate of often concerned with the rate of dissolution of a agitation, area of solute available etc. In the latter drug from a formulated product such as a tablet or a case this will change greatly in a conventional tablet capsule, as well as with the dissolution rates of pure formulation, as the tablet breaks up into granules solids.

Later chapters in this book should be con- and then into primary powder particles as it comes sulted for information on the influence of formula- into contact with water. Particle size will change during undissolved solid dissolution process, because large particles will become smaller and small particles will eventually disappear.

Compacted masses of solid may also disintegrate into smaller particles Dispersibility of powdered If particles tend to form coherent masses in the solid in dissolution medium dissolution medium then the surface area available for dissolution is reduced.

This effect may be overcome by the addition of a wetting agent Porosity of solid particles Pores must be large enough to allow access of dissolution medium and outward diffusion of dissolved solute molecules Cs solubility of solid in Temperature Dissolution may be an exothermic or an endothermic dissolution medium.

Molecular structure of solute See previous comments on sodium salts of weak acids and esterification Crystalline form of solid See previous comments on polymorphism and solvation Presence of other compounds See previous comments on common ion effect, complex formation and solubilizing agents C, concentration of solute in Volume of dissolution medium If volume is small C will approach Cs if volume is large C solution at time t may be negligible with respect to Cs i.

This is known as the intrinsic dissolution rate Rotating basket method IDR , which is the rate of mass transfer per area of This method is described in most pharmacopoeias dissolving surface and typically has the units of mg for the determination of the dissolution rates of crrr2 mirr1. IDR should be independent of boundary drugs from tablets and capsules. Details of the appa- layer thickness and volume of solvent if sink condi- ratus and methods of operation are given in these tions are assumed.

Basically these methods involve placing the tablet or capsule inside a stainless steel wire basket, which is rotated at a fixed speed while Thus IDR measures the intrinsic properties of the drug only as a function of the dissolution medium, immersed in the dissolution medium, which is con- tained in a wide-mouthed cylindrical vessel, the e. Techniques for measuring IDR are discussed briefly bottom of which is either flat or spherical. Samples below and in more detail in Chapter 8.

Measurement of dissolution rates Paddle method Many methods have been described in the literature, particularly in relation to the determination of the This is another official method.

The dissolution rate of release of drugs into solution from tablet and vessel described in the rotating basket method, i. Agitation is provided by a these dosage forms see Chapters 17, 27, 29 and These classifications agitation is commenced. The following brief descriptions non-disintegrating disc which is mounted in a holder are given as examples of the more commonly used so that only one face of the disc is exposed. The methods that are illustrated in Figure 2.

Samples of the dissolution medium The methodology of Levy and Hayes forms the basis are removed after known times, filtered and assayed. In their initial work they used a In both methods it is assumed that the surface area cm3 beaker containing dm3 of dissolution from which dissolution can occur remains constant.

The stirrer was immersed to a depth of 27 mm mined. This is the intrinsic dissolution rate and into the dissolution medium and rotated at 60 rpm. In the liquid were removed at known times, filtered and these latter methods the surface area of the drug that assayed.

As these changes are not usually mon- round-bottomed flask is used instead of a beaker. Thus, standardization in the results. This latter point is particularly impor- of the experimental methodology is essential if such tant, as dissolution rate tests are usually performed comparisons are to be meaningful. Description Approximate weight of solvent g Reference should be made therefore to later chapters necessary to dissolve 1 g of solute in this book for information on the dissolution methods applied to these other dosage forms.

The amount of substance that passes into solution in order to establish the equilibrium at constant temper- interrelationships between such terms and approxi- ature and pressure and so produce a saturated solution mate solubilities are shown in Table 2.

It is possi- Speculation on what is likely to be a good solvent ble to obtain supersaturated solutions but these are is usually based on the 'like dissolves like' principle, unstable and the excess solute tends to precipitate that is, a solute dissolves best in a solvent with similar readily. The concept traditionally follows two rules: Methods of expressing solubility 1. Polar solutes dissolve in polar solvents.

Solubilities may be expressed by means of any of the 2. Non-polar solutes dissolve in non-polar solvents. They are expressed most dipole moment. Chemical groups that confer polarity commonly, however, in terms of the maximum mass to their parent molecules are known as polar groups.

If Pharmacopoeias give information on the approx- the solvent is A and the solute B and the forces of imate solubilities of official substances in terms of attraction are represented by A-A, B-B and A-B, the number of parts by volume of solvent required one of three conditions will arise: Unless otherwise specified, 1. If A-A A-B, i. As an example, benzene is almost completely insoluble in water.

Attraction between water molecules is very strong, so that Prediction of solubility water exists as aggregates, which have a similar Probably the most sought-after information about form to ice, floating in a matrix of free solutions in formulation problems is 'what is the molecules.

It may be visualized as 'icebergs' best? Theoretical prediction of precise solubilities is Molecules are continually moving from sea to an involved and occasionally unsuccessful operation, icebergs and from icebergs to sea. The attraction but from a knowledge of the structure and properties between benzene molecules arises from weak van of solute and solvent an educated guess can be der Waals forces, so that although very little made.

This is best expressed in subjective terms, energy is required to disperse benzene such as 'very soluble' or 'sparingly soluble'. Often molecules, discrete benzene molecules are particularly in pre- or early formulation this is all unable to penetrate the closely bound water the information that the formulator requires. The aggregates. If B-B A-A, the solvent will not be able to that the strength of these forces can be expressed in break the binding forces between solute molecules terms of a solubility parameter.

The initially intro- and disperse them. This situation would apply if duced parameters, which are concerned with the you tried to dissolve sodium chloride in benzene. A conducting solvent, such as water, of the behaviour of a small number of hydrocarbons, would be required to overcome the attraction they only provide a broad qualitative description of the between solute molecules. The concept has been extended, however, by the a solution. Hansen parameters and interaction parameters, that The above is a simplified overview of the situation.

Studies on Similar types of interrnolecular force may contribute solubility parameters are sometimes reported in the to solute-solvent, solute-solute and solvent-solvent pharmaceutical literature. The use of dielectric con- interactions.

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The attractive forces exerted between stants as indicators of solvent power has also polar molecules are much stronger, however, than received attention, but deviations from the behaviour those that exist between polar and non-polar mole- predicted by such methods may occur.

Mixtures of liquids are often used as solvents. If Consequently, a polar solute will dissolve to a greater the two liquids have similar chemical structures, e. If the liquids have dissimilar struc- relatively weak. In addition, the forces of attraction tures, e. The solvent properties of this type of system because the solute-solvent forces will again be rela- are not so simply related to its composition as in the tively weak. Thus, solvents for non-polar solutes tend previous case.

The above considerations are often expressed very generally as 'like dissolves like', i. Such a gen- type encountered in pharmaceutical practice. The eralization should be treated with caution, because the pharmacist should therefore be aware of the general interrnolecular forces involved in the process of disso- method of determining the solubility of a solid in a lution are influenced by factors that are not obvious liquid and the various precautions that should be from a consideration of the overall polarity of a mole- taken during such determinations.

Determination of the solubility of a solid in a Solubility parameter Attempts have been made to liquid define a parameter that indicates the ability of a liquid The following points should be observed in all solu- to act as a solvent.

The most satisfactory approach is based on the concept that the solvent power of a liquid bility determinations: The solvent and the solute must be pure. A saturated solution must be obtained before tional comments that referred to Eqn 2. The method of separating a sample of saturated usually an endothermic one, i.

If this type of satisfactory. The method of analysing the solution must be nullify the constraint imposed upon it, e. This tendency is an example of Le 5. Temperature must be adequately controlled. Chatelier's principle.

Thus, a rise in temperature will lead to an increase in the solubility of a solid with a A saturated solution is obtained either by stirring positive heat of solution. Conversely, in the case of excess powdered solute with solvent for several hours the less commonly occurring systems that exhibit at the required temperature until equilibrium has exothermic dissolution, an increase in temperature been attained, or by warming the solvent with an will give rise to a decrease in solubility.

It is essential that some referred to as solubility curves, are often used to undissolved solid should be present at the comple- describe the effect of temperature on a given system.

Some examples are shown in Figure 2. Most of the curves are continuous; however, abrupt changes in A sample of the saturated solution is obtained for slope may be observed with some systems if a change analysis by separating it from the undissolved solid.

Its solubility therefore change in the equilibrium between dissolved and increases with rise in temperature until Above this temperature the solid is con- 2.

The filtration process has been simplified by the The solubility therefore exhibits a change from a introduction of membrane filters that can be used in positive to a negative slope as the temperature conjunction with conventional syringes fitted with exceeds the transition value. The amount of solute contained in the sample of saturated solution may be determined by a variety of methods, e. The selection of an appropriate method is affected by the natures of the solute and the solvent and by the concentration of the solution.

Factors affecting the solubility of solids in liquids Knowledge of these factors, which are discussed below together with their practical applications, is an important aspect of the pharmacist's expertise.

Additional information, which shows how some of these factors may be used to improve the solubilities and bioavailabilities of drugs, is given in Chapters 21 and 17, respectively. Temperature Earlier discussion centred on Eqn 2. The addi- Fig. Molecular structure of solute It should be appreci- incorporation of one or more water-miscible cosol- ated from the previous comments on the prediction vents, so that a solution containing mg in 10 mL of solubility that the natures of the solute and the and suitable for parenteral administration in the solvent will be of paramount importance in deter- treatment of anaerobic infection, can be obtained.

It should Crystal characteristics: For example, molecules or ions in a crystal lattice. These inter- the introduction of a hydrophilic hydroxyl group can actions will depend on the relative positions and ori- produce a large improvement in water solubility, as entations of the molecules in the crystal. When the evidenced by the more than fold difference in conditions under which crystallization is allowed to the solubilities of phenol and benzene.

These different crystalline forms of the water. The overall interaction between solute and same substance, which are known as polymorphs, solvent is markedly increased and the solubility con- consequently possess different lattice energies, and sequently rises.

A specific example of this effect is this difference is reflected by changes in other prop- provided by a comparison of the aqueous solubilities erties; for example, the polymorphic form with the of salicylic acid and its sodium salt, which are 1: Other less stable or The reduction in aqueous solubility of a parent metastable forms will tend to transform into the drug by its esterification may also be cited as an most stable one at rates that depend on the energy example of the effects of changes in the chemical differences between the metastable and the stable structure of the solute.

Such a reduction in solubility forms. Polymorphs are explained more fully in may provide a suitable method for: Chapter 9. The effect of polymorphism on solubility is partic- 1. The the gastrointestinal tract, e. In addition, con- Nature of solvent: In addition, the Many drugs exhibit polymorphism, e. Examples of the be employed. Such mixtures are often used in phar- importance of polymorphism with respect to the maceutical practice to obtain aqueous-based systems bioavailabilities of drugs and to the occurrence of that contain solutes in excess of their solubilities in crystal growth in suspensions are given in Chapters pure water.

This is achieved by using cosolvents such 17 and 23, respectively. For example, the aqueous solu- Chapter 9 may also lead to an increase in the solubil- bility of metronidazole is about mg in 10 mL. Chien has shown, however, that the solubility In addition to the effect of polymorphism the lattice of this drug can be increased exponentially by the structures of crystalline materials may be altered by.

The resultant solids acidic drug or a salt of such a drug is reduced then are called solvates; the phenomenon is referred to the proportion of unionized acid molecules in the correctly as salvation and sometimes incorrectly and solution increases. Precipitation may therefore occur confusingly as pseudopolymorphism.

The alter- because the solubility of the unionized species is less ation in crystal structure that accompanies solvation than that of the ionized form. Conversely, in the case will affect AHcl so that the solubilities of solvated and of solutions of weakly basic drugs or their salts pre- unsolvated crystals will differ. Such If water is the solvating molecule, i. Consequently, ionized solutes is extremely important with respect hydrated crystals tend to exhibit a lower aqueous sol- to the ionization of weakly acidic and basic drugs as ubility than their unhydrated forms.

This decrease in they pass through the gastrointestinal tract and expe- solubility can lead to precipitation of drugs from rience pH changes between about 1 and 8.

This will solutions. This aspect is discussed in vates are often greater than those of the unsolvated some detail, elsewhere in this book and the reader is forms. Examples of the effects of solvation and the referred to Chapters 3 and 17 in particular. If the pH of the solu- where S is the solubility of small particles of radius r, tion is known then Eqn 2. This effect may be significant in the storage of In the case of basic drugs the corresponding pharmaceutical suspensions, as the smaller particles relationship is given by Eqn 2.

As the small particles disappear, the overall solubility of the suspended drug will decrease and the larger particles will grow.

The occurrence of Common ion effect The equilibrium in a saturated crystal growth by this mechanism is of particular solution of a sparingly soluble salt in contact with importance in the storage of suspensions intended undissolved solid may be represented by: The increase in solubility with decrease in particle size ceases when the particles have a very small radius, and any further decrease in size causes a From the Law of Mass Action the equilibrium decrease in solubility.

It has been postulated that this constant K for this reversible reaction is given by change arises from the presence of an electrical Eqn 2.

As the concentration increases, the effects of interi- If each molecule of the salt contains more than onic association are no longer negligible and the one ion of each type, e. If tration of the ions, i. This is known as the common ion effect. The reason Ks is a constant, it follows that Ks' must also vary for this is explained below.

Thus, in a system The solubility of a sparingly soluble electrolyte may containing a sparingly soluble electrolyte without a be increased by the addition of a second electrolyte common ion, the ionic strength will have an appre- that does not possess ions common to the first, i.

The definition of the solubility product of a spar- From Eqn 2. In fact, the concentration tion of ions produced at equilibrium, as indicated by solubility product Ks' will become larger and larger Eqn 2. The exact thermodynamic relationship expressed by Eqn solubility of AB will therefore increase as the con- 2.

The activity of a particular ion may Law of Mass Action. In Effect of non-electrolytes on the solubility of electrolytes general this has a lower value than the actual con- The solubility of electrolytes depends on the dissoci- centration, because some ions produced by dissocia- ation of dissolved molecules into ions.

The ease of tion of the electrolyte are strongly associated with this dissociation is affected by the dielectric constant oppositely charged ions and do not contribute so of the solvent, which is a measure of the polar nature effectively as completely unallocated ions to the of the solvent. Liquids with a high dielectric constant properties of the system. At infinite dilution the wide e.

Effect of electrolytes on the solubility of non-electrolytes where w is the mass of gas dissolved by unit volume of Non-electrolytes do not dissociate into ions in solvent at an equilibrium pressure p and k is a pro- aqueous solution, and in dilute solution the dissolved portionality constant. Although Henry's law is most species therefore consists of single molecules.

Their applicable at high temperatures and low pressures, solubility in water depends on the formation of weak when solubility is low it provides a satisfactory intermolecular bonds hydrogen bonds between their description of the behaviour of most systems at molecules and those of water.

The presence of a very normal temperatures and reasonable pressures, unless soluble electrolyte e. Equation of which have a marked affinity for water, will reduce 2. This The solubility of most gases in liquids decreases as effect is important in the precipitation of proteins. This provides a means of Complex formation The apparent solubility of a removing dissolved gases.

For example, water for solute in a particular liquid may be increased or injections free from either carbon dioxide or air may decreased by the addition of a third substance which be prepared by boiling water with minimal exposure forms an intermolecular complex with the solute.

The solubility of the complex will determine the The presence of electrolytes may also decrease the apparent change in the solubility of the original solubility of a gas in water by a 'salting out' process, solute. Use is made of complex formation as an aid which is caused by the marked attraction exerted to solubility in the preparation of solution of mer- between electrolyte and water.

The latter is not very soluble in water but is soluble in aqueous solutions of potas- sium iodide because of the formation of a water- Solubility of liquids in liquids soluble complex, K2 HgI4. The components of an ideal solution are miscible in Solubilizing agents These agents are capable of all proportions. Such complete miscibility is also forming large aggregates or micelles in solution observed in some real binary systems, e.

In and water, under normal conditions. However, if one aqueous solution the centre of these aggregates of the components tends to self-associate because resembles a separate organic phase and organic the attractions between its own molecules are greater solutes may be taken up by the aggregates, thus pro- than those between its molecules and those of the ducing an apparent increase in their solubilities in other component, i.

This phenomenon is known as solubiliza- Raoult's law occurs, the miscibility of the compo- tion. A similar phenomenon occurs in organic sol- nents may be reduced.

The extent of the reduction vents containing dissolved solubilizing agents, depends on the strength of the self-association and, because the centre of the. Thus, partial miscibility may be observed in organic solvent. If polar solutes are taken up into some systems, whereas virtual immiscibility may be these regions their apparent solubilities in the exhibited when the self-association is very strong organic solvents are increased.

In cases where partial miscibility occurs under normal conditions the degree of miscibility is usually Solubility of gases in liquids dependent on the temperature. This dependency is The amount of gas that will dissolve in a liquid is indicated by the phase rule, introduced by J. Eqn 2. In passive diffusion, which is influence absorption rate and onset of action, with thought to control the absorption of most drugs, the solutions acting faster than suspensions, which in turn process is driven by the concentration gradient that generally act faster than capsules and tablets.

Dosage exists across the cellular barrier, with drug molecules forms can thus be listed in order of time of onset of passing from regions of high to those of low concen- therapeutic effect Table 1.

However, all drugs, irre- tration. Lipid solubility and the degree of ionization of the drug at the absorbing site influence the rate of dif- Table 1.

Several specialized transport mechanisms are different dosage forms postulated, including active and facilitated transport. Once absorbed, the drug can exert a therapeutic effect Time of onset of action Dosage forms either locally or at a site of action remote from that of Seconds i. In the latter case the drug has to be Minutes i. The overall effect of temperature variation on the degree of miscibility in these systems is usually described by means of phase diagrams, which are graphs of temperature versus composition at con- stant pressure.

For convenience of discussion of their phase diagrams the partially miscible systems may be divided into the following types. Systems showing an increase in miscibility with Fig. This difference becomes more marked as Systems showing upper and lower critical the temperature decreases, and the positive deviation solution temperatures may then result in a decrease in miscibility sufficient to cause the separation of the mixture into two The decrease in miscibility with increase in temper- phases.

Each phase consists of a saturated solution of ature in systems having a lower GST is not one component in the other liquid. Such mutually indefinite. Above a certain temperature, positive saturated solutions are known as conjugate deviations from Raoult's law become important and solutions.

This behaviour produces a closed- miscible liquids may be followed either by shaking phase diagram, as shown in Figure 2. Systems showing a decrease in miscibility with rise in temperature A few mixtures, which probably involve compound formation, exhibit a lower critical solution tempera- ture GST , e. The formation of a compound produces a negative deviation from Raoult's law, and miscibility therefore increases as the temperature falls, as shown in Figure 2.

The effect of temperature on miscibility is of use in the preparation of paraldehyde enemas, which usually consist of a solution of paraldehyde in Fig. Cooling the mixture during prepara- water system at kPa; standard atmospheric pressure. In some mixtures where an upper and lower CST are expected, these points are not actually observed, as a phase change by one of the components occurs where aA and aB are the activities of the solute in sol- before the relevant CST is reached.

For example, the vents A and B, respectively. When the solutions are ether-water system would be expected to exhibit a dilute, or when the solute behaves ideally, the activi- lower CST, but water freezes before the temperature ties may be replaced by concentrations CA and CB: The effects of added substances on critical solution temperatures where the constant K is known as the distribution coefficient or partition coefficient.

In the case of It has already been stated that a CST is an invariant sparingly soluble substances K is approximately point at constant pressure.

These temperatures are equal to the ratio of the solubilities SA and. SB of very sensitive to impurities or added substances. In the solute in each liquid, i. The increase in miscibility of two liquids caused by the addition of a third substance is referred to as In most other systems, however, deviation from ideal blending. For example, if the The use of propylene glycol as a blending agent, solute exists as monomers in solvent A and as dimers which improves the miscibility of volatile oils and in solvent B, the distribution coefficient is given by water, can be explained in terms of a ternary phase Eqn 2.

This is a triangular plot which indicates the tion of the dimeric form is used: If the dissociation into ions occurs in the aqueous layer, B, of a mixture of immiscible liquids, then the degree of dissociation a should be taken into Distribution of solutes between account, as indicated by Eqn 2. For example, a partition constant temperature, it is found that the solute is coefficient of 2 for a solute distributed between oil distributed between the two liquids in such a way and water may also be expressed as a partition that the ratio of the activities of the substance in each coefficient between water and oil of 0.

This can be liquid is a constant. The tribution law, which can be expressed by Eqn 2. Upper Approx. Solubility of solids in solids i.

When the If two solids are either melted together and then latter carrier solid is dissolved away the molecules or cooled or dissolved in a suitable solvent, which is small crystals of insoluble drug may dissolve more then removed by evaporation, the solid that is rede- rapidly than a conventional powder because the posited from the melt or the solution will either be a contact area between drug and water is increased.

The one-phase solid solution or a two-phase eutectic rate of dissolution and, consequently, the bioavailabil- mixture.

Complete miscibility of two solid com- ponents is only achieved if: Parenteral Sci. Noyes, A. As Barton, A. CRC Press Inc. Thus, dilute solutions of solids in solids may Beerbower, A. Pharmaceutical Handbook, 3rd edn Ed. Unlike a solution, a simple eutectic consists of an Pharmaceutical Press, London. Rowlinson, J. It deals solutions 33 mainly with the physicochemical properties of solu- Ideal solutions: Raoult's law 34 tions that are important with respect to pharmaceu- Real and non-ideal solutions 35 tical systems.

These aspects are covered in sufficient lonization of solutes 35 detail to introduce the pharmaceutical scientist to Hydrogen ion concentration and pH 36 these properties. Much is published elsewhere in far Dissociation or ionization constants and pK"a 36 greater detail and any reader requiring this addi- Buffer solutions and buffer capacity 38 tional information is referred to the bibliography at Colligative properties 38 the end of the chapter.

Although a variety of different types can exist, solutions of pharmaceutical interest. In addition, the solutes are pre- dominantly solid substances. Consequently, most of the comments made in this chapter are made with solutions of solids in liquids in mind.

However, appro- priate comments on other types, e. Vapour pressures of solids, liquids and solutions An understanding of many of the properties of solu- tions requires an appreciation of the concept of an ideal solution and its use as a reference system, to which the behaviours of real non-ideal solutions can be compared.

This concept is itself based on a consid- eration of vapour pressure. The present section is therefore included as an introduction to the later dis- cussions on ideal and non-ideal solutions.

The kinetic theory of matter indicates that the the solution. It will also depend on the relative thermal motion of molecules of a substance in its strengths of the attractive forces between adjacent gaseous state is more than adequate to overcome the solvent molecules on the one hand and between attractive forces that exist between the molecules. Therefore, Thus, the molecules will undergo a completely as the intermolecular forces between solid solutes random movement within the confines of the con- and liquid solvents tend to be relatively strong, such tainer.

The situation is reversed, however, when the solute molecules do not generally escape from the temperature is lowered sufficiently so that a con- surface of a solution and contribute to the vapour densed phase is formed. Thus, the thermal motions pressure. In other words, the solute is generally non- of the molecules are now insufficient to overcome volatile and the vapour pressure arises solely from completely the intermolecular attractive forces and the dynamic equilibrium that is set up between the some degree of order in the relative arrangement of rates of evaporation and condensation of solvent molecules occurs.

If the intermolecular forces are so molecules contained in the solution. In a mixture of strong that a high degree of order, which is hardly miscible liquids, i. Thus, the effects of Ideal solutions: Raoult's law interactions between the permanent and induced The concept of an ideal solution has been intro- dipoles, i.

Abstract Controlled release delivery is available for many routes of administration and offers many advantages as microparticles and nanoparticles over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development.

Keywords: polymers, copolymers, biomaterials, biodegradable, microparticle, nanoparticle, pharmaceutical dosage forms, particle engineering design, manufacture 1. Introduction Biodegradable and biocompatible materials for pharmaceutical dosage forms have enabled the advancement of pharmaceuticals by providing better therapy and disease state management for patients through controlled release drug delivery, particularly as microparticles and nanoparticles.

Controlled release delivery is available for many routes of administration and offers many advantages over immediate release delivery. Controlled Drug Release Technology of Drugs In order to achieve efficient disease management, the concentration of released drugs from polymeric matrices should be within the therapeutic window with minimal fluctuation in blood levels over prolonged periods of time at the intended site of action [ 1 — 3 ].

The release of drug can be controlled by diffusion, erosion, osmotic-mediated events or combinations of these mechanisms [ 4 , 5 ]. Typically, a triphasic release pattern is observed, consisting of an initial burst [ 4 ], primarily attributed to drug precipitates at the particle surface and surface pores in the polymer, and the osmotic forces in highly water-soluble peptide formulations [ 6 ], a lag period depending on the molecular weight and polymer end-capping [ 5 ] and finally erosion-accelerated release [ 6 ].

Considering release rate control as a key parameter, a decrease in particle size i. Also, higher porosity of the particles inducing a larger inner surface can increase the influx of the release medium into the particles and, thereby, facilitate the drug diffusion rate [ 7 ]. In addition, the specific properties of the polymer matrix e.

Therefore, switching to a different molecular weight or an end group capped polymer, and the use of block copolymers will alter the diffusion and drug release rate [ 10 , 11 ].As the radius and length of the cap- initial acceleration period is followed by motion at a illary as well as the volume flowing are constants for uniform terminal velocity when the gravitational force a given viscometer, then is balanced by the viscous drag.

If the preservative exhibits lipophilic properties e. Whelan, J. Rheology -- 5. Be the first. Most of the effects of these factors are included in the summary given in Table 2.

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