5
`
`Dosage Form Design: Pharmaceutic
`lngredie~ts, Product Formulation, and
`Current Good Manufacturing Practice
`
`THE PROPER design of a dosage form requires
`consideration of the physical, chemical and bio(cid:173)
`logical charactertstics of all of the drug sub(cid:173)
`stances and phannaceutic ingredients to be used
`in fabricating the product. The drug and phar(cid:173)
`maceutic materials utilized must be compatible
`with one another to produce a drug product that
`is stable, efficacious, attractive, easy to admin(cid:173)
`ister and safe. The product should be manufac(cid:173)
`tured under appropriate measures of quality
`control and packaged in containers that contrib(cid:173)
`ute to product stability. The product should be
`labeled to promote correct use and be stored
`under conditions that contribute to maximum
`shelf life.
`Methods for the preparation of specific types
`of dosage fonns are described in subsequent
`chapters. This chapter presents some general
`considerations regarding phannaceutic ingre(cid:173)
`dients, drug product formulation, stability, pres(cid:173)
`ervation, flavoring, coloring, packaging, storage,
`and standards for good manufacturing practice.
`
`Phannaceutic Ingredients
`In order to prepare a drug substance into a
`final dosage form, phannaceutic ingredients are
`required. For example, in the preparation of
`pharmaceutical solutions, one or more solvents
`are utilized to dissolve the drug substance, pre(cid:173)
`servatives may be added to prevent microbial
`growth, stabilizers may be used to prevent drug
`
`decomposition, and colorants and ftavorants
`added to enhance product appeal. In the prep(cid:173)
`aration of tablets, diluents or fillers are com(cid:173)
`monly added to increase the bulk of the for(cid:173)
`mulation, binders to cause the adhesion of the
`powdered drug and phannaceutic substances.
`antiadherents or lubricants to assist the smooth
`tableting process, disintegrating agents to pro(cid:173)
`mote tablet break-up after administration, and
`coatings to improve stability, control disintegra(cid:173)
`tion, or to enhance appearance. Ointments,
`creams, and suppositories achieve their char(cid:173)
`acteristic features due to the pharmaceutic bases
`which are utilized. Thus, for each dosage form,
`the phannaceutic ingredients establish the pri(cid:173)
`mary features of the ploduct, and contribute to
`the physical form. texture, stability, taste and
`overall appearance.
`Table 5-1 presents the principal categories of
`pharmaceutic ingredients, with examples of
`some of the official agents currently used.
`
`General Considerations in Drug
`Product Formulation
`In dealing with the problem of formulating a
`drug substance into a proper dosage form. re(cid:173)
`search phannacists employ knowledge that has
`been gained through experience with other sim(cid:173)
`ilar drugs and through the proper utilization of
`the disciplines of the physical, chemical, and
`biological sciences. The early stages of any new
`
`83
`
` Ex. 1016
`
`Page 1 of 34
`
`Mylan Ex. 1016
`IPR Petition - USP 6,316,023
`
`

`

`84
`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice
`
`Alkalinizing Agent
`
`Adsorbent
`
`Aerosol Propellant
`
`Table 5-1. Examples of Official Pharmaceutic: Ingredients
`Ingredient Type
`Definition
`Example$
`Used in liquid preparations to provide acetic acid
`Acidifying Agent
`acidic. medium for product stability.
`hydrochloric acid
`niaic acid
`Used in liquid preparations to provide ammonia solution
`alkaline medium fbr product stabiltiy.
`ammonium carbonate
`potassium hydroxide
`sodium borate
`sodium carbonate
`sodium hydroxide
`trolamine
`An agent capable of holding other mol· powdered cellulose
`ecules onto its surface by physical or activated charcoal
`chemical (chemisorption) means.
`An agent reSponsible for developing the dtch.lorodifluoromethane
`pressure within an aerosol container and dichlorotet:rafluoroethane
`expelling the product when the valve is aichloromonofiuoromethane
`opened.
`An agent which is employed to displace nitrogen
`air in a hermetically sealed container to
`enhance product stability.
`Used in liquid and semi·solid prepara· benzoic acid
`tions to prevent the growth of fungi.
`butylparaben
`ethylparaben
`methylparaben
`propylparaben
`sodium benzoate
`sodium propionate
`
`Air Displacement
`
`Antifungal Preservative
`
`Antimicrobial Preseruati:ve
`
`Antioxidant
`
`Buffering Agent
`
`Used in liquid and semi·solid prepara· benzalkonium chloride
`lions to prevent the growth of microor- benzethonium chloride
`ganisrns.
`benzyl alcohol
`cetylpyridinium chloride
`chlorobutanol
`phenol
`phenylethyl alcohol
`phenylmercuric nitrate
`thimerosal
`An agent which inhibits oxidation and ascorbyl palmitate
`thus is used to prevent the deterioration butylated hydroxyantsole
`of preparations by the oxidative process. butylated hydroxytoluene
`hypophophorous acid
`monothioglycerol
`propyl gallate
`sodium bisUlfite
`sodium formaldehyde
`sulfoxylate
`sodium metabisulfite
`Used to resist change in pH upon dilu- potassium metaphosphate
`tion or addition of acid or alkali.
`potassium phosphate,
`monobasic
`sodium acetate
`
` Ex. 1016
`
`Page 2 of 34
`
`

`

`Table S,...l. Continued
`Ingredient Type
`Chelating Agent
`
`Colorant
`
`Emulsifying Agent
`
`Encapsulating Agent
`
`Flavorant
`
`Humectant
`
`Levigating Agent
`
`Ointment Base
`
`So/:vent
`
`Stiffening Agent
`
`Defi:ni.tiJm
`Examples
`A substance that forms stable complexes edetate disodium
`with metals. Chelating agents are used edetic acid
`in some liquid phannaceuticals as sta-
`bilizers to complex heavy metals which
`might promote instahillty. In such use
`they are also called sequestering agents.
`Used to impart color to phannaceulical erythrosine (FD&C Red
`preparations.
`No.3)
`caramel
`ferric oxide, red
`Used to promote and maintain the dis· acacia
`persian of finely subdivided particles of sorbitan monooleate
`a liquid in a vehicle In which it is im· polyoxyethylene 50 stearate
`miscible.
`Used to fonn thin shells for the purpose gelatin
`of enclosing a drug substance or drug cellulose acetate phthalate
`formulation for ease of administration.
`Used to impart a pleaS.ant fLavor and anise oil
`often odor to a phannaceutical prepara- cinnamon oil
`cocoa
`tion.
`menthol
`orange oil
`peppermint oil
`vanillin
`Used to prevent the drying out of prep- glycexin
`arations-particula.lry ointments and propylene glycol
`creams-due to the agent's ability to re- sorbitol
`tain moisture.
`A liquid used as an intervening agent to mineral oil
`reduce the particle size of a drug powder
`by gr.inding together, usually in a mortal:
`The semisolid vehicle into which drug lanolin
`substances may be incorpoated In pre- hydrophilic ointment
`paring medicated ointments.
`polyethylene glycol omtment
`petrolatum
`hydrophilic petrolatum
`White ointment
`yellow ointment
`rose water ointment
`An agent used to dissolve another pbar- alcohol
`maceutic substance or a drug in the isopropyl alcohol
`preparation of a solution.
`mineral oil
`oleic acid
`peanut oil
`purified water
`water for injection
`sterile water for injection
`sterile water for inigation
`Used to increase the thickness or hard- cetyl alcohol
`ness of a pharmaceutical preparation, paraffin.
`white wax
`usually an ointment.
`yellow wax
`
`·
`
` Ex. 1016
`
`Page 3 of 34
`
`

`

`86
`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice
`
`Table 5-L Continued
`Ingredient Type
`Suppository Base
`
`Surf(J.Ctant
`( surf(J.Ce· active agent)
`
`Suspending Agent
`
`Sweetening Agent
`
`Tablet Anti.adherents
`
`Tablet Binders
`
`Tablet and Capsule Diluent
`
`Tablet CQllting Agent
`
`Tablet Distntegrant
`
`Tablet Glidant
`
`Tablet Lubricant
`
`Definition
`Examples
`Used as a vehicle into which drug sub- cocoa butter
`stances are incorporated in the prepa- polyethylene glycols
`(mixtures)
`ration of suppositories.
`Substances which adsorb to surlaces or bem:alkonium chloride
`interfaces to reduce surlace or interfacial nonoxynol I 0
`tension. May be used as wetting agents, octoxynol9
`detergents or emulsifying agents.
`polysorbate 80
`sodium lauryl sulfate
`sorbitan monopalmitate
`
`A viscosity inareasing agent used to :re- agar
`duce the rate of sedimentation of dis- bentonite
`persed particles.
`carboxymethylcellulose
`sodium
`hydroxypropyl methyl-
`cellulose
`methylcellulose
`tragacanth
`xanthan gum
`
`Used to impart sweetness to a prepara- dextrose
`tion.
`saccharin sodium
`sucrose
`
`Agents which prevent the sticking of tab- magnesium stearate
`let formulation ingredients to punches talc
`and dies in a tableting machine during
`production.
`Substances used to cause adhesion of acacia
`powder particles in tablet granulations. ethylcellulose
`gelatin
`methylcellulose
`Inert substances used as fillers to create microcrystalline cellulose
`the desired bulk, flow properties, and lactose
`compression characteristics in the prep•
`aration of tablets and capsules.
`Used to coat a formed tablet for the pur- cellulose acetate phthalate
`pose of protecting against drug decom- sucrose
`position by atmospheric oxygen or hu- pharmaceutic~~e
`midity, to provide a desired release (shellac in ~coho!)
`pattern for the drug substance after
`administration, to mask the taste or odor
`of the drug substance, or for aesthetic
`purposes.
`
`Used in solid dosage fonns to promote cornstarch
`the disruption of the solid mass into sodium alginate
`smaller particles which a:re mo:re readily
`dispersed or dissolved.
`
`Agents used in tablet and capsule for- colloidal silica
`mulations to improve the flow properties cornstarch
`of the powder mixture.
`talc
`
`. Substances used in tablet formulations calcium stearate
`to :reduce friction during tablet compres- magnesium stearate
`stearic acid
`sion.
`
` Ex. 1016
`
`Page 4 of 34
`
`

`

`Dosage Form Design: Ingedienta, Product Formulation, Manufacturing Practice
`
`87
`
`rable S-1. Continued
`Ingredient Type
`Tablet Polishing Agent
`
`Tonicity Agent
`
`Vehicle
`
`Definition
`Examples
`Used to impart an attractive sheen to c:atnaubawa.x
`coated tablets.
`white wax
`Used to render a solution similar in os- dextrose
`motic characteristics to physiologic sodium chloride
`ftuids.
`A cmying agent for a drug substance. F1.avured!Sweetened
`Acac.ia Syrup
`Aromatic Elixir
`Chmy Syrup
`Cocoa Syrup
`Orange Syrup
`Syrup
`Oleaginous
`Com Oil
`Mineral Oil
`Peanut Oil
`Sesame Oil
`Sterile
`Bacteriostatic Sodium
`Chloride Injection
`Bacteriostatic Water
`for Injection
`
`fonnulation involves studies to collect basic in(cid:173)
`fonnation on the physical and chemical char(cid:173)
`acteristics of the drug substance to be prepared
`into pharmaceutical dosage forms. These basic
`studies comprise the preformulation work
`needed before actual product formulation be(cid:173)
`gins.
`
`Prefonnulation Stl,ldies1
`
`Physical Description
`It is important to have an understanding of
`the physical desGription of a drug substance
`plior to dosage form development The majortty
`of drug substances in use today occur as solid
`matertals. Most of them are pure chemical com(cid:173)
`pounds of either crystalline or amorphous con(cid:173)
`stitution. Uquid drugs are used to a much lesser
`extent; gases, even less frequently. Of the official
`medicinal gases, nitrous oxide and cyclopropane
`are used as general anesthetics by inhalation
`and oxygen and carbon dioxide are respiratory
`aids.
`Among the few liquid medicinal agents are
`the following:
`
`Amyl nitrtte, vasodilator by inhalation
`Castor oil, cathartic
`
`Clofibrate, antihyperli.pidemic
`Dimercaprol. antidote for arsenic, gold, and mer(cid:173)
`cury poisoning
`EtbchlorvynoL hypnotic
`Glycerin, cathartic in suppository form
`Mineral oil, cathartic
`Nitroglycertn (as tablets), anti-anginal
`Par.Udehyde, sedative-hypnotic
`Paramethadione, anticonvulsant
`Prochlorperazine, tranquilizer and antiemetic
`Propylhexedline, vasoconstrictor by nasal in(cid:173)
`halation
`Tetrachloroethylene, anthelmintic
`Undecylenic acid, fungistatic agent
`
`Uquid drugs pose an interesting problem in
`dosage form design. Many of them are volatile
`substances and as such must be physically
`sealed from the atmosphere to insure their con(cid:173)
`tinued presence. Amyl nitrite, for example, is a
`clear yellowish liquid that is volatile even at low
`temperatures and is also highly flammable. It is
`maintained for medicinal purposes in small
`sealed glass cylinders wrapped with gauze or
`another suitable material. When amyl nitrtte is
`administered, the glass is broken between the
`fingertips and the liquid wets the gauze cover(cid:173)
`ing, producing vapors that are inhaled by the
`patient requirtng vasodilation. Propylhexedrtne
`
` Ex. 1016
`
`Page 5 of 34
`
`

`

`88
`
`Dosage Farm Design: Ingredients, Product .l'ormwauur£, mu ..... J .... ·-· •• .., •• --· .•
`
`provides another example of a volatile liqUid
`drug that must be contained in a closed system
`to maintain its presence. This drug is used as a
`nasal inhalant for its vasoconstrictor action A
`cylindrical roll of fibrous material is impregnated
`with propylhexedrine, and the saturated cylin(cid:173)
`der is placed :in a suitable, generally plastic,
`sealed nasal inhaler. The inhaler's cap must be
`securely tightened each time it is used. Even
`then, the inhaler maintains its effectiveness for
`only a limited period of time due to the volatil(cid:173)
`ization of the drug.
`Another problem associated with liquid drugs
`is that those intended for oral administration
`cannot generally be fonnulated into tablet form,
`the most popular fQtlll of oral medication, with(cid:173)
`out undertaking major chemical modification of
`the drug. An exception to this is the liquid drug
`nitroglycerin which is formulated into tablet tri(cid:173)
`turates which disintegrate within seconds after
`placement under the tongue. However, because
`the drug is volatile, it has a tendency to escape
`from the tablets during storage and it is critical
`that the tablets be stored in tightly sealed glass
`containers. For the most part, when a liquid drug
`is to be administered orally and a solid dosage
`form is desired, two approaches are used. First,
`the liquid substance may be sealed in a soft gel(cid:173)
`atin capsule. Paramethadione and ethchlorvynol
`are examples of liquid drugs commercially avail(cid:173)
`able in capsule form. 2 Secondly, the liquid drug
`may be developed into a solid ester or salt form
`that will be suitable for tableting or drug encap(cid:173)
`sulating. For instance, scopolamine hydrobrom(cid:173)
`ide is a solid sait of the liquid drug scopolamine
`and is easily produced into tablets.
`For certain liquid drugs, especially those em(cid:173)
`ployed orally in la:rge doses or applied topically,
`their liquid nature may be of some advantage in
`therapy. For example, 15-cml doses of mineral oil
`may be administered conveniently as such. Also,
`the liquid nature of undecylenic acid certainly
`does not hinder but rather enhances its use top(cid:173)
`ically in the treatment of fungus infections of
`the skin. However, for the most part, solid ma(cid:173)
`terials are preferred by pharmacists in formu(cid:173)
`lation work because of their ease of preparation
`into tablets and capsules.
`Formulation and stability difficulties arise less
`frequently with solid dosage forms than with
`liquid phannaceutical preparations, and for this.
`reason many new drugs first reach the market
`as tablets or dry filled capsules. Later, when the
`
`pharmaceutical problems are resolved, a liquid
`fonn of the same drug may be marketed. This
`procedure, when practiced, is doubly advanta(cid:173)
`geous, since for the most part physicians and
`patients alike prefer small, generally tasteless,
`accurately dosed tablets or capsules to the anal~
`ogous liquid fonns that may have an unpleasant
`taste and are likely to be measured by the patient
`with highly vartable household spoons. There(cid:173)
`fore, marketing a drug in solid form first is more
`practical for the manufacturer and also suits the
`majority of patients. It is estimated that tablets
`and capsules comprise the dosage form dis(cid:173)
`pensed 70% of the time by community phar(cid:173)
`macists, with tablets dispensed twice as fre(cid:173)
`quently as capsules.
`
`Microscopic Examination
`Microscopic examination of the raw drug sub(cid:173)
`stance is an important step in prefonnulation
`work. It gives an indication of particle size and
`particle size range of the raw material as well as
`the ccystal structure. Photomicrographs of the
`initial and subsequent batch lots of the drug
`substance can provide impo.rtarit information
`should problems arise in formulation processing
`attributable to changes in particle or crystal
`characteristics of the drug.
`
`Particle Size
`Cert:am physical and chemical properties of
`drug substances are affected by the particle size
`distribution, including drug dissolution rate, bio(cid:173)
`availability, content uniformity, taste, texture,
`color, and stability. In addition, properties such
`as :flow characteristics and sedimentation rates,
`among others, are also important factors related
`to particle size. It is essential to establish as early
`as possible how the particle size of the drug sub(cid:173)
`stance may affect fonnulation and product ef.
`ficacy. Of special interest is the effect of particle
`size on the drug's absorption Particle size has
`been shown to significantly influence the oral
`absorption profiles of certain drugs as griseo(cid:173)
`fulvin, nitrofurantoin, spironolactone, and pro(cid:173)
`caine penicillin.
`Satisfactory content uniformity in solid dosage
`forms depends to a large degree on particle size
`and the equal distribution of the active ingre(cid:173)
`dient throughout the formulation.
`There are several methods available to eval(cid:173)
`uate particle size and distribution including siev(cid:173)
`ing or screening, microscopy, sedimentation,
`and streanl scanning. For powders in the range
`
` Ex. 1016
`
`Page 6 of 34
`
`

`

`Dosage Form Design: Ingedients, Product Formulation, Manufacturtng ~actu:e
`
`ou
`
`of approximately 44 microns and greater, sieving
`or screening is the most widely used method of
`size analysis. The difficulty with using this
`method early in the prefonnulation program is
`the requirement of a relatively large sample size.
`The main advantage of the sieve method is sim(cid:173)
`plicity, both in technique and equipment re(cid:173)
`quirements. Optical microscopy is frequendy
`the first step in the determination of particle size
`and shape for the new drug substance. This is
`usually a qualitative assessment since quanti(cid:173)
`tation by the microscope technique is tedious
`and time consuming. A key element in utilizing
`the microscope for particle size determination is
`preparation of the slide. It must be representa(cid:173)
`tive of the bulk of the material and be properly
`suspended and thoroughly dispersed in a suit(cid:173)
`able liquid phase. In order to do a quantitative
`particle size evaluation a min1mum of 1000 of
`the particles should be counted.
`Sedimentation techniques utilize the relation(cid:173)
`ship between rate of fall of particles and their
`size. Techniques utilizing devices that contin(cid:173)
`uously collect a settling suspension are used.
`These methods share the disadvantage of the
`microscope technique in that it is tedious to ob(cid:173)
`tain the data Also, proper dispersion, consistent
`sampling, temperature control, and other ex(cid:173)
`perimental variables must be carefully con(cid:173)
`trolled in order to obtain consistent and reliable
`results.
`Stream scanning is a valuable method for de(cid:173)
`tenni.n:ing particle size distribution of powdered
`drug substances. This technique utilizes a fiuid
`suspension of particles which pass the sensing
`zone where individual particles are sized,
`counted, and tabulated Sensing units may be
`based on light scattering or transmission, as well
`as conductance. Two popular units in the phar(cid:173)
`maceutical industry for this purpose are the
`Coulter Counter and Hiac Countel: Both units
`electronically size; count, and tabulate the in(cid:173)
`dividual particles that pass through the sensing
`zone. This technique has obvious advantages in
`that data can be generated in a relatively short
`time with reasonable accuracy. Thousands of
`particles can be counted in seconds and used to
`determine the size distribution curve. All stream
`scanning units convert the particles to effective
`diameter, and therefore, have the shortcoming
`of not providing information relative to particle
`shape. Nevertheless, stream scanning methods
`are powerful tools and can be used for evaluation
`
`of such parameters as crystal growth in suspen(cid:173)
`sion formulations.
`
`Partition Coefficient and Dissociation Constant
`
`As discussed in the previous chapter, in order
`to produce a biological response, the drug mol(cid:173)
`ecule must first cross a biological membrane.
`The biological membrane acts as a lipid barrier
`to most drugs and permits the absorption of lipid
`soluble substances by passive diffusion while
`lipid insoluble substances can diffuse across the
`barrier only with considerable difficulty, if at all.
`The interrelationship of the dissociation con(cid:173)
`stant, lipid solubility, and pH at the absorption
`site and absorption characteristics of various
`drugs are the basis of the pH-partition theory.
`The determination of the degree of ionization or
`pKa value of the drug substance is an important
`physical-chemical chancteristic relative to eval(cid:173)
`uation of possible effects on absorption from var(cid:173)
`ious sites of administration
`Dissociation constant or pKa is usually deter(cid:173)
`mined by potentiometric titration.
`
`Polymorphism
`
`An important factor on fonnulation is the crys(cid:173)
`tal or amorphous fonn of the drug substance.
`Polymorphic forms usually exhibit different
`physical-chemical properties including melting
`point and solubility. The occw:rence of poly(cid:173)
`morphic forms with drugs is relatively common
`and it has been estimated that polymorphism is
`exhibited by at least one-third of all organic com(cid:173)
`pounds.
`In addition to the polymorphic forms in which
`compounds may exist, they also can occur in
`non-crystalline or amorphous fonns. The energy
`required for a molecule of drug to escape from
`a crystal is much greater than required to escape
`from an amorphous powder. Therefore, the
`amorphous form of a compound is always more
`soluble than a corresponding crystal fonn.
`Evaluation of crystal structure, polymorph(cid:173)
`ism, and solvate fonn is an important prefor(cid:173)
`mulation activity. The changes in crystal char(cid:173)
`acteristics can influence bioavailability,
`chemical and physical stabiltiy, and have im(cid:173)
`portant implications in dosage form process
`functions. For example, it can be a significant
`factor relating to the tableting processes due to
`flow and compaction behaviors, among others.
`Various techniques are used in determining
`crystal properties. The most widely used meth-
`
` Ex. 1016
`
`Page 7 of 34
`
`

`

`90
`
`Dosage Form Design: Ingredients. Product Formulation, Manufacturing Practice
`
`ods are hot stage microscopy, thermal analysis,
`infrared spectroscopy, and x-ray diffraction.
`
`Solubility
`An important physical-chemical property of a
`drug substance is solubility, especially aqueous
`system solubility. A drug must possess some
`aqueous solubility for therapeutic efficacy. In
`order for a drug to enter the systemic circulation
`to exert a therapeutic effect, it must first be in
`solution. Relatively insoluble compounds often
`exhibit incomplete or erratic absorption. If the
`solubility of the drug substance is less than de(cid:173)
`sirable, consideration must be given to improve
`its solubility. The methods to accomplish this
`will depend on the chemical nature of the drug
`and the type of drug product under considera(cid:173)
`tion. For example, if the drug substance is acidic
`or basic, solubility may be influenced by changes
`in pH.
`However, there are many drug substances for
`which pH adjustment is not an effective means
`of improving solubility. Weak acidic or basic
`drugs may require extremes in pH that are out(cid:173)
`side accepted physiologic limits or may cause
`stability problems with formulation ingredients.
`Adjustment of pH usually has little effect on the
`solubility of non-electrolytes. In many cases, it
`is desirable to utilize co-solvents or other tech(cid:173)
`niques such as complexation, micronization, or
`solid dispersion to improve aqueous solubility;
`A drug's solubility is usually detennined by
`the equilibrium solubility method, by which an
`excess of the drug is placed in a solvent and
`shaken at a constant temperature over a pro(cid:173)
`longed period of time until equilibrium is ob(cid:173)
`tained. Chemical analysis of the drug content in
`solution is performed to determine degree of sol(cid:173)
`ubility.
`
`Dissolution
`Variations in the biological activity of a drug
`substance may be brought about by the rate at
`which it becomes available to the organism. In
`many instances, dissolution rate, or the time it
`takes for the drug to dissolve in the fluids at the
`absorption site, is the rate-limiting step in the
`absorption process. This is true for drugs ad(cid:173)
`ministered orally in solid forms such as tablets,
`capsules or suspensions, as well as drugs ad(cid:173)
`ministered intramuscularly in the form of pellets
`or suspensions. When the dissolution rate is the
`rate-limiting step, anything which affects it will
`also affect absorption. Consequently, dissolution
`
`rate can affect the onset. intensity, and duration
`of response, and control the overall bioavaila:bil(cid:173)
`ity of the drug from the dosage form, as dis(cid:173)
`cussed in the previous chapter:
`As discussed previously, the dissolution rate
`of drugs may be increased by increasing the
`drug.'s particle size. It may also be increased by
`increasing its solubility in the diffusion layer:
`The most effective means of obtaining higher
`dissolution rates is to use a highly water soluble
`salt of the parent substance. Although a soluble
`salt of a weak add will subsequently precipitate
`as the free acid in the bulk phase of an acidic
`solution, such as gastric fluid, it will do so in the
`form of fine particles with a large surface area.
`The dissolution rates of chemical compounds
`are generally determined by two methods: the
`constant surface method which provides the in(cid:173)
`trinsic dissolution rate of the agent, and partic(cid:173)
`ulate dissolution in which a suspension of the
`agent is added to a fixed amount of solvent with(cid:173)
`out exact control of surface area.
`The constant surface method utilizes a com(cid:173)
`pressed disc of known area. This method elim(cid:173)
`inates surface area and surface electrical
`charges as dissolution variables. The dissolution
`rate obtained by this method is tenned the in(cid:173)
`trinsic dissolution rate, and is characteristic of
`each solid compound and a given solvent under
`the fixed experimental conditions. The value is
`generally expressed as milligrams dissolved per
`minute centimeters squared (mglmin/cm2). It
`has been suggested that this value is useful in
`predicting probable absorption problems due to
`dissolution rate. In particulate dissolution, a
`weighed amount of powdered sample is added
`to the dissolution medium in a constant agitation
`system. This method is frequently used to study
`the influence of particle size, surface area. and
`excipient& upon the active agent Occasionally,
`an inverse relationship of particle size to disso(cid:173)
`lution is noted due to the surface properties of
`the drug. In these instances, surface charge and!
`or agglomeration results in the reduced particle
`size form of the drug presenting a lower effective
`surface area to the solvent due to incomplete
`wetting or agglomeration.
`Early studies should include the effects of
`pharmaceutic ingredients on the dissolution
`characteristics of the drug substance.
`
`Membrane Permeability
`Modern preformulation st1,1dies include an
`early assessment of passage of drug molecules
`across biological membranes.
`
` Ex. 1016
`
`Page 8 of 34
`
`

`

`Dosage Form Design: lngedients, Product Formulation, Manufacturing Practice
`
`ll.l
`
`Data obtained from the basic physical-chem(cid:173)
`ical studies, specifically, pKa., solubility, and dis(cid:173)
`solution rate provide an indication of absorption
`expectations.
`To enhance these data, a technique utilizing
`the "everted intestinal sac'' may be used in eval(cid:173)
`uating absorption characteristics of drug sub(cid:173)
`stances. In this method, a piece of intestine is
`removed from an intact animal, everted, filled
`with a solution of the drug substance, and the
`degree and rate ofpassage of the drug through
`the membrane sac is detennined. Through this
`method, bot;h passive and active transport can
`be evaluated.
`In the latter stages of preformulation testing
`or early formulation studies, animals and man
`must be studied to assess the absoxption effi(cid:173)
`ciency, phannacokinetic paramc;!ters and to es(cid:173)
`tablish possible in vitro/in vivo correlation for
`dissolution and bioavailability.
`
`Stability
`One of the most important activities of pre(cid:173)
`formulation work is the evaluation ef the phys(cid:173)
`ical and chemical stability of the pure drug sub(cid:173)
`stance. It is essential that these initial studies
`be conducted using drug samples of known pu(cid:173)
`rity. The presence of impurities can lead to er(cid:173)
`roneous conclusions in such evaluations. Sta(cid:173)
`bility studies conducted in the preformulation
`phase include solid state stability of the drug
`alone, solution phase stability, and stability in
`the presence of expected excipients.
`Initial investigation begins through knowl(cid:173)
`edge of the drug's chemical structure which
`allows the preformulation scientist to anticipate
`the possible degradation reactions.
`Chemical instability of medicinal agents may
`take many forms, since the drugs in use today
`are of such diverse chemical constitution.
`Chemically, drug substances are alcohols, phen(cid:173)
`ols, aldehydes, ketones, esters, ethers, acids,
`salts, alkaloids, glycosides, and others, each with
`reactive chemical groups having different sus(cid:173)
`ceptibilities toward chemical instability. Chem(cid:173)
`ically, the most frequently encountered destruc(cid:173)
`tive processes are hydrolysis and oxidation.
`Hydrolysis is a. solvolysis process in which
`(drug) molecules interact with water molecules
`to yield breakdown products of different chem(cid:173)
`ical constitution. For example, aspirin or ace(cid:173)
`tylsalicylic acid combines with a water molecule
`and hydrolyzes into one molecule of salicylic
`acid and one molecule of acetic acid:
`
`Aspirin
`
`Sa lic:y II~ A~id
`
`Acetic Acid
`
`The process of hydrolysis is probably the most
`important single cause of drug decomposition
`mainly because a great number of medicinal
`agents are esters or contain such other group(cid:173)
`ings as substituted amides, lactones, and lac(cid:173)
`tams, which are susceptible to the hydrolytic
`process.
`Another destructive process is oxidation. The
`oxidative process is destructive to many drug
`types, including aldehydes, alcohols, phenols,
`sugars, alkalOids, and unsaturated fats and oils.
`Chemically, oxidation involves the loss of elec(cid:173)
`trons from an atom or a molecule. Each electron
`lost is accepted by some other atom or molecule,
`thereby accomplishing the reduction of the re(cid:173)
`cipient In inorganic chemistry, oxi.dat:ion is ac(cid:173)
`companied by an increase in the positive valence
`of an element-for example, ferrous ( + 2) oxi-(cid:173)
`dizing to ferric ( +3). In organic chemistry, ox(cid:173)
`idation is frequently considered synonymous
`with the loss of hydrogen (dehydrogenation)
`from a molecule. The oxidative process fre(cid:173)
`quently involves free chemical radicals, which
`are molecules or atoms containing one or more
`unpaired electrons, as molecular (atmospheric)
`oxygen (-0--Qe) and free hydroxyl (<>H). These
`radicals tend to take electrons from other chem(cid:173)
`icals, thereby oxidizing the donor. Many of the
`oxidative changes in pharmaceutical prepara(cid:173)
`tions have the character of autoxidations. Au(cid:173)
`toxidations occur spontaneously under the ini(cid:173)
`tial influence of atmospheric oxygen and
`proceed slowly at first and then more rapidly as
`the process continues. The process has been de(cid:173)
`scribed as a type of chain .reaction commencing
`by the union of oxygen with the drug molecule
`and continuing with a fre