9. Preformulation Testing

7/28/2019 9. Preformulation Testing

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The discovery and development ofNCEs (New chemical entities)

into a stable, bioavailable, marketable drug products is long butreally a rewarding process.

Preformulation testing is the first step in the rational development

of dosage forms.

Those studies which are necessary to fully characterize molecules

during the discovery and development process so that the NCEs

have the appropriate properties are called as Preformulation

studies.

These studies commences when a newly synthesized drug shows

sufficient pharmacologic promise in animal models to warrant

evaluation in man.

I. What are the Preformulation studies


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It can be defined as an investigation of physical and chemicalproperty of a drug substance alone and when combined with

excipients.

Preformulation is also phase of research and development

process where research scientist characterize physical,

chemical and mechanical aspect of new drug under

investigation in order to develop stable, sage & effective

dosage form.

A. Definition


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Need for Preformulation studies

Preformulation studies are done-

I. To facilitate drug property based designs

II. To give NCEs the highest possibility of success

III. Understanding or the knowledge of deficiencies such as

molecules weakness, decay mechanism or the drug

decomposition ( aspirin undergoing ester hydrolysis)

occurring during formulation process and thus can be

eradicated

IV. To fulfill goal of designing optimum drug delivery systems


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ORGANOLEPTIC PROPERTIES

A typical preformulation program should begin with the description

of the drug substance.

The color, odor, and taste of the new drug must be recorded using

descriptive terminology.


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Color:

A record of color of the early batches is very useful in

establishing appropriate specifications for later production.

When the color attributes are undesirable or variable,

incorporation of a dye in the body or coating of the final product

could be recommended.

Odors and tastes

Characteristic to particular drug.

If taste is considered as unpalatable, consideration ought to be

given to the use of a less soluble chemical form of the drug, ormay be suppressed by using appropriate flavors and excipients

or by coating the final product (must be screened for theirinfluence on the stability and bioavailability of the active drug).


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Bulk characterization

Bulk properties for the solid form, such as particle size, bulk

density and surface morphology are likely to change duringprocess development.

Therefore, comprehensive characterization of all Preformulation

bulk lots is necessary to avoid misleading predictions of stabilityor solubility.

Outline

A. Crystallinity and polymorphism

B. Hygroscopicity

C. Fine particle characterization

D. Bulk density

E. Powder flow properties


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Crystal properties and polymorphism


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Crystal habit: description of the outer appearance of a crystal

Internal structure: molecular arrangement within the solid

Characterization of a solid form involves:

1. Verifying that the solid is the expected chemical compound

2. Characterizing the internal structure and then

3. Describing the habit of the crystal

A single internal structure for a compound can have several

different habits, depending on the environment for growing

crystals.

Changes with internal structure usually alter the crystal habit.


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Different habits of crystals

Internal structure

Platy

Equant or massive

Needle or acicular

Bladed

Tabular

Prismatic and so on

Repeated spacing of atomsHave less energy

Need lot of energy to break

crystalline form

So solubility is low

randomly placed molecules have more energy

need less energy to break

molecules

so solubility is high

Amorphous


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Internal structure


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Polymorphism

Many drug substances can exist in more than one distinct crystalline

form with different space lattice arrangements (internal lattices).This property is known as polymorphism. The different crystal forms

are called polymorphs.

Occasionally a solid crystallizes, entrapping solvent molecules in aspecific lattice position and in a fixed stoichiometry, resulting in a

solvate or pseudo-polymorph.

Many solids may be prepared in a particular polymorphic form via

appropriate manipulation of conditions of crystallization

Nature of the solvent

Temperature

Rate of cooling etc


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Amorphous form: Many times, a solute precipitates out of a solution

so that the molecules in the resulting solid are not ordered in a

regular array but in a more or less random arrangement. This state is

known as the amorphous form.

Usually shock cooling, a sudden change in the composition of the

solvent of crystallization, or lyophilization results in an amorphous

form.

Characteristics:

Usually higher thermodynamic energy than corresponding

crystalline forms

Solubilities as well as dissolution rates are generally greaterUpon storage tend to revert to more stable forms.

During bulk processing/within dosage forms thermodynamic

instability is the major disadvantage for developing an amorphous

form.


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Polymorphs

Enantiotropic

Reversible- change into anotherby change in temperature or

pressure e.g. sulphur

Monotropic

Unstable at all temperature orpressure, e.g. Glyceryl strearates

Amorphous > Metastable > stable

Stable

Low energy

High melting point

Low solubility

Low rate of dissolution

Metastable

High energy

Low melting point

High solubility

High rate of dissolution


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A. Crystal characteristics & bioavailability

Different polymorphic forms different in the dissolution rates and

solubilities for a given drug

When the absorption of a drug is dissolution rate-limited, a more

soluble and faster dissolving form may be utilized to improve the

rate and extent of bioavailability.

Example

polymorphs of chloramphenicol palmitate

Comparative blood level data were obtained in human following oraladministration of 1.5 gm of pure A and pure B forms of chloramphenicol palmitate

and their mixtures. Data show that

I. Pure, more soluble B form was most bioavailable

II. Pure, less soluble A form was least bioavailable.

III. Mixture- fell between these two extremes and was directly proportional to

concentration of B.


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Example

Chlortetracycline hydrochloride

Among alpha & beta forms of chlortetracycline hydrochloride, more solublebeta form is more bioavailable.

Dissolution curves of the and

forms of chlortetracycline HClfrom

compressed disks in water at 37C.

Plasma levels after intraduodenal

administration the andforms of

chlortetracycline HCl to rabbits.


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B. Crystal characteristics & chemical stability

For drugs prone to degradation in the solid state, the physical forms

of the drug influences the rate of degradation.

Example

Aztreonam, a monobactum antibiotic, exists in needle like and

dense spherical - crystalline forms.

In presence of high humidity (37C/75% RH)-

forms: undergoes - lactum hydrolysis more readily with a half-

life of about 6 months- forms: stable for several years under identical conditions.


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Two crystal forms of a labile drug could exhibit widely different

solid-state stabilities, a Preformulation scientist might consider

changing the crystal forms to alleviate and possibly eliminate a

stability problem.


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Under stress conditions,

I. the anhydrous crystalline form of this experimental drug degraded

rapidly with a half-life of about 8 weeks.

II. A solvate form of the drug under the same conditions was essentially

stable

III. Desolvation of the solvate caused by excessive heat resulted in a newcrystal form distinct from the anhydrous and solvate forms. The

desolvated form under the test conditions degraded most rapidly.

This test illustrates not only the possible use of a polymorphicform to solve a stability problem but also the importance of

controlling processing variables so that the integrity of the

selected form is maintained.


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C. Crystal characteristics & tableting behavior

In a typical tableting operation, flow and compaction behaviors of the

powder mass to be tableted are important considerations. Theseproperties are related to the morphology, tensile strength and density

of powder bed.

Two polymorphic forms of the same drug could differ significantly with

respect to these properties. The morphology of a crystal also dependson crystal habit (outer appearance of crystal).

When the environment in which crystal grow changes the external

shape of the crystals without altering their internal structure, then a

different habit results. Crystal habit is influenced by-

Presence of an impurity

Concentration

Rate of crystallization


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Tablet compaction process -

Packing of particles by diffusion into void spaces

Elastic and plastic deformation

Fracture and cold working and

Finally compression of solid material

One or more of these sub processes may be affected by crystal form and

habit.

Example:

I. Different polymorphs of sulfathiazole, barbitone and aspirin differed

significantly in their compression characteristics.

II. The crystalline form of Indomethacin yielded tablets with better

hardness characteristics than the amorphous form.

Investigation of polymorphism and crystal habit of a drug is desirable

during its Preformulation evaluation especially when the active ingredient

is expected to constitute the bulk of the tablet mass.


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C. Crystal characteristics & physical stability

Although a drug substance may exist in two or more polymorphic

forms only one form is thermodynamically stable at a given

temperature and pressure. The other forms would convert to stable

form with time. This transformation may be rapid or slow. When the

transformation is not rapid, the thermodynamically unstable form is

referred to as a metastable form.

A metastable form nevertheless may exhibit sufficient chemical and

physical stability under shelf conditions to justify its use for reasons

of better dissolution or ease of tableting.


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Polymorphic transformations can occur during grinding, granulating,

drying, and compressing operations.

As for example-

I. Digoxin, spironolactone and estradiol are reported to undergo

polymorphic transformations during the comminution process.

II. Phenylbutazone undergoes polymorphic transformation as a

result of grinding and compression.

Granulation, since it entails the use of solvent, can lead to a solvateformation. On the other hand, if the molecule is initially a solvate,

the drying step in the process may cause transformation to an

anhydrous crystalline or amorphous form.


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Polymorphism and polymorphic stability is also needed to

predict long-term physical stability of dosage forms.

As for example-

I. Cappinglike cracking in tablets of anhydrous crystalline

carbochromen hydrochloride upon storage under high-

humidity conditions. This was determined to be due totransformation of the anhydrous form into a dihydrate.

Even when the stable form is the form of choice, it is advisable

to monitor the crystal form of each lot of raw material.


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In case of combination product like multi vitamin preparation:

In case of calcium pantothenate the preferred form is theCrystalline Form.

In the preparation of multivitamin tablets,

calcium pantothenate is granulated with a few other vitamins

and appropriate excipients. An amorphous form of calcium

pantothenate is known which readily reverts to the stable form

when wetted with a variety of solvents used as granulating

Solvents.

Use of amorphous form in multivitamin tablets

prepared by a granulation process is not desirable because thepolymorphic transformation renders the granulating mass sticky

and making further granulation virtually impossible.


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D. Techniques for studying Crystal properties

Various techniques are available for the investigation of the solid

state. These include-

I. Microscopy (including hot-stage microscopy)

II. Infrared sprctrophotometry

III. Single-crystal X-rayIV. X-ray powder diffraction

V. Thermal analysis

VI. Dilatometry


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Hygroscopicity


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Tendency to absorb moisture from air. E.g. water soluble

drugs.

Deliquescent material (materials which become liquid by

absorbing moisture from air) absorbs sufficient water from

air. E. g. NaCl on humid day.

Hygroscopic compounds stored in a well closed

container preferable with a desiccant.


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Equilibrium moisture content may influenceI. the flow and compression characteristics of powders

II. hardness of the final tablets and granulations.

The amount of moisture absorbed by a fixed weight of

anhydrous sample in equilibrium with the moisture in the

air at a given temperature is referred to as equilibrium

moisture content.

Sorption isothermsEquilibrium moisture content of drug & excipients as a function

of a relative vapor pressure.

Determined by placing samples in desiccators having different

humid condition.Importance- rate and extent of moister sorption is determined

and proper processing & storage conditions of drug may be

selected on basis of this isotherm.


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Surface dissolution of drugs:

A solid dissolves in the absorbed layer of water when relative

humidity of atmosphere exceeds that of its saturated solution.The latter condition is called critical relative humidity RH0.

Crystalline substances not expected to dissolve below RH0.

Effect of mechanical processing:Grinding, milling, micronization, compaction etc. can induce

changes in their reactivity toward water vapor.

As a result the surface dissolution of drug may occur at alower humidity which may lead to chemical and physical

instability problems during storage.


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Effect of moisture content in excipients:

Physicochemical properties of solid dosage forms can be

influenced by moisture content in excipients.

Example:

Water exists as two forms bound (solid like) and free of

excipients like

cellulose & starch derivatives.Free water content minimization may avoid stability

problem.

Removal of unbound water reduces the ability of

microcrystalline cellulose and compressible sugar to act as

direct compaction materials. Because free water is needed toprovide plasticity to the system.

Free water on the external surface of powders can also affect

powder flow.


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Monitoring moisture these methods can be used:

Gravimetric test

TGA (Thermo Gravimetric Analysis)Karl Fischer titration

Gas chromatography.


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Flow ability


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During Preformulation study, flow ability characteristic should

be studied especially when the anticipated dose of the drug is

large.

Flow properties of powders are critical for

I. Efficient tableting operationII. to assure efficient mixing and

III. Acceptable weight uniformity.


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Angle of repose:

The angle between the free surface of the static heap and the

horizontal plane can achieve a certain maximum value for agiven powder.

Common way of expressing flow characteristics of powders

and granulation

For most pharmaceutical powders, the angle of repose value

range from 25 to 45, For most pharmaceutical powders, the

angle of repose value range from 25 to 45 lower values

indicating better flow characteristics.

Angle of repose depends on the method used. Falling

particles may distort the heap. Apparatus used by pilpel is

free from this type of distortion.


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Drawbacks of Angle of repose:

Lack of sensitivity. Example- sodium chloride, spray dried

lactose, and fast flow lactose showed similar angles of

repose. But their rate of flow through 6 cm orifice were quitedifferent.

Use more than one method for proper characterization such

as compressibility index, shear cell, flow through an orifice.


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Poor flow drugs

Acicular crystals (because of cross-binding), material with

low density and materials with a static charge exhibit poorflow.

Improvement of flow ability:

Acicular crystals: grinding process can improve flow

For other powders and granulations: incorporation of

lubricant or glidant

Pre granulation


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Compactibility or

Compressibility


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In Preformulation study

Compressibility and Compactibility of new drug alone & in

combination of some common excipients should be obtained

as a part of evaluation.

Hydraulic press: simplest ways to generate such data. Powders

that form hard compact under applied pressure without

exhibiting any tendency to cap or chip to considered as readily

compactable.


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Compactibilityof a powder is the ability of powdered material

to be compressed into a tablet of specific tensile strength.

Compactibilityof pharmaceutical powder is characterized bystudying tensile strength, indentation hardness etc. of

compacts prepared under various pressure.

Tensile strength:

For determination of tensile strength, compacts are placed radially

and axially between two platens and forces required to fracture thecompacts are measured. (radial and axial tensile strength)

Indicate bonding strengths of compacts in two direction

Related to their tendency towards capping

To evaluate the type and concentration of binders necessary to

improve compactibility.

d


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Hardness:

Defined as the resistance of a solid to deformation

Hardness is primarily related to its plasticity.

Commonly measured by static impression method (Brinell test)

The brinell hardness number (BHN) is then calculated by

using-


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Compressibilityof a powder is the ability to decrease in

volume under pressure.

Compressibility of powder is characterized from the density-compression pressure relationship according to Heckel plot.

Significance-

Information regarding extent of compression

Minimum pressure required to cause deformation of solid

Nature of deformation (plastic deformation, brittle fracture)


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Wettability


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Important property with regard to formulation of a solid dosage

form.

It may influence granulation of solids, penetration of dissolutionfluids into tablets and granules & adhesion of coating materials to

tablets.

Method:

I. Wettability is often described in terms of contact angle,measured by placing drops of liquids on compacts of

materials.

More hydrophobic higher is the contact angle: value above

90 (using water) implies little or no spontaneous wetting.

II. The distance a liquid penetrates into a bed of powders or a

compact is measured. (Washburn)


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Crystal structures can also influence the contact angle.

For example, a and S forms of chloramphenicol palmitate

have contact angles of 122 and 1080 , respectively.

Problems associated with Wettability of powder:

Poor dissolution rate & Low adhesion of film coating

May be solves by intimate mixing with hydrophilic excipients

or by incorporating a surfactant in the formulation.


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Solubility


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Solid drugs administered orally for systemic activity must

dissolve in the gastrointestinal fluids prior to their absorption.

The rate of dissolution of drugs in gastrointestinal fluids could

influence the rate and extent of their absorption.

Inasmuch as the rate of dissolution of a solid is a function of

its solubility in the dissolution medium, the latter couldinfluence absorption of the relatively insoluble drugs.

The solubility of every new drug must be determined as a

function of pH over the physiological pH range of 1 to 8.If the solubility is considered too low or too high. efforts to

alter it may be undertaken.


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A. Determination of Solubility

I. Semi quantitative determination of the solubility can be

made by adding the solute in small incremental amounts toa fixed volume of the solvent. After each addition, the

system is vigorously shaken and examined visually for any

un-dissolved solute particles. When some solute remains

un-dissolved, the total amount added up to that point serves

as a good and rapid estimate of solubility.

II. When more quantitative data are needed, a suspension of

the solute in the solvent is shaken at constant temperature.

Samples are withdrawn periodically, filtered, and theconcentration of the solute in the filtrates is determined by a

suitable method. Sampling is continued until consecutive

samples show the same concentration.


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A. Determination of Solubility

III. Solubility of an acidic or basic drug is pH -dependent and, as

mentioned earlier, must be determined over the pH range 1to 8. Since such compounds favor their own pH environment

dictated by their pKa values, it becomes necessary to adjust

the pH values of their saturated solution.

IV. The saturation solubility of a poorly soluble compound is not

reached in a reasonable length of time unless the amount of

solid used is greatly in excess of that needed to saturate a

given volume of solvent.

V. Difficulty is also encountered in the determination of

solubility of metastable forms that transform to more stable

forms when exposed to solvents. Here a method based on

the determination of intrinsic dissolution rates is applicable


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pH-Solubility Profile

S f


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pH-Solubility Profile

The degree of ionization and therefore the solubility of

acidic and basic compounds depends on the pH of themedium.

Saturation solubility:

For ionizable compounds a solution may be saturated withrespect to one species or the other depending on pH.

The saturation solubility for such compounds at a

particular pH is the sum total of solubility of ionized and

unionized forms.

St = [BH+] + [B], St total molar solubility, BH

+ is the

protonated species & B is the free base.

H h H f i l bili


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pH max ,the pH of maximum solubility:

The pH at which the solution is saturated with respect to

both the ionized and unionized forms

St , pH = pH max= [BH+]s + [B]s , here subscript s denotes saturation.

Total solubility for weak base:

I. In pH region where the solubility of protonated form is

limiting

II I H i h th l bilit f th f b i


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II. In pH region where the solubility of the free base is

limiting

Total solubility for weak acid:

where [A ] and [AH] denote concentrations of ionized and

unionized forms.

C S l bilit P d t & i ff t


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C. Solubility Product & common ion effect

In a saturated solution of a salt with some undissolved solid,

there exists an equilibrium between the excess solid and theions resulting from the dissociation of the salt in solution. For

a hydrochloride salt represented as BH+CI-, the equilibrium

is

where BH+ and Cl- represent the hydrated ions in solution.

Ksp

Ksp is the solubility product for the protonated species and

chloride counter ion, or.

Ksp = [BH+].[Cl-]

For an ionizable drug as mentioned earlier total solubility S


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For an ionizable drug as mentioned earlier total solubility ST

is the Sum total of [BH+]s and [B]. Since [BH+]s[B].Equation for a hydrochloride salt reduces to -

This equation dictates that total solubility of a HCl salt woulddecrease with an increase in the chloride ion concentration.

This phenomenon is known as common ion effect.

Example: The solubility of Doxycyline hydrochloride Dihydrate in

aqueous medium of pH 2 or less logarithmically decreases as afunction of pH because of corresponding increase in chloride ion

concentration. In gastric juice (pH range 1 to 2, chloride ion conc.

0.1M to 0.15M) Doxycyline HCl Dihydrate has a solubility of ~

4mg/ml, which is less than its solubility in distilled water.

Significance


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Significance:

The solubility product for each ionizable compound with either

sodium or chloride ions should be evaluated to detect potential in

vivo problems with dissolution and/or absorption.

Since the gastric contents are high in chloride ion concentration.

The common ion effect phenomenon suggests that one shoulduse salts other than the hydrochloride to benefit fully from the

enhanced solubility due to a salt form.

Despite this. many drugs are used as hydrochloride salts. This is

because solubilities of most hydrochloride salts in the presenceof chloride lon concentration normally encountered in vivo are

sufficiently high. The suppression of solubility due to common ion

effect under these conditions is not of sufficient magnitude to

affect dissolution or bioavailability of these compounds.


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Solubilization


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Solubilization

When the drug substance under consideration

is not an acidic or basic compound,

or

when the acidic or basic character of the compound is not

amenable to the formation of a stable salt,

Then other means of enhancing the solubility may beexplored.

Approaches / examples


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I. Use of a more soluble Metastable polymorph to enhance

bioavailability of orally administered solids.

II. Use of complexation: Riboflavin in solution complexes with

xanthines, resulting in an increase in the apparent solubility

of the vitamin

III. Use of water-soluble polymers to form high-energy

coprecipitates: Griseofulvin is a water-insoluble, neutral

polyethylene glycol antifungal antibiotic. Dispersions and

solid solutions of griseofulvin in PEG 4000, 6000, and

20,000 dissolve significantly more rapidly than the wettedmicronized drug. Subsequent studies with the PEG 6000

dispersion showed that, in humans, the dispersed drug was

more than twice as available as from commercially available

tablets containing the micronized drug.


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In the majority of cases efforts to alter solubilities of drugs are

undertaken to improve the solubility. Occasionally, however, a

less soluble form is desired.

In the case of clindamycin, the less soluble pamoate salt is

preferred over the soluble hydrochloride hydrate to avoid theproblem of the unpleasant taste of the drug.

Likewise, when a drug is inactivated by the acidity of gastric

fluids, a less soluble form is preferred.

Importance of knowledge on solubilrty of a drug substance


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Importance of knowledge on solubilrty of a drug substance

Helps in making some judgment concerning its bioavailability.

Useful in the development of appropriate media for dissolution

testing.

For development of an injectable dosage form for certainpharmacological and comparative bioavailability studies.

In the investigation of dissolution of drugs insoluble in a purely aqueous

medium, a cosolvent may be used to provide sink conditions. In these

situations, knowledge of solubility in water-miscible organic solvents suchas lower molecular weight alcohols and glycols is useful. The latter data

are also of use to a formulator in the development of dosage forms of

drugs that are administered in very small doses. Here the drug is often

dispersed among the excipients as a solution in an appropriate solvent.

Importance of knowledge on solubility of a drug


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Importance of knowledge on solubility of a drug

substance

Solubility data are also useful to the formulator in choosing

the right solvent for the purposes of granulation and coating.

The use of a granulating solvent with a very high capacity to

dissolve the active ingredient can lead to a phenomenonknown as case hardening. Here the solute migrates and

deposits on the periphery of granules during the drying

operation.


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DISSOLUTION


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Dissolution of a drug particle is controlled by several

physicochemical properties-

Chemical formCrystal habitParticle sizeSolubility

Surface area andWetting properties

The absorption of solid drugs administered orally can be


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The absorption of solid drugs administered orally can be

depicted by the following flowchart:

where kd and ka are rate constants for the dissolution and

absorption processes, respectively.

When dissolution is the significantly slower of the two

processes (Le, , kd ka) the absorption is described as

dissolution rate-limited.

Intrinsic Dissolution


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Intrinsic Dissolution

The dissolution rate of a solid in its own solution is

adequately described by the Noyes-Nernst equation:

During the early phase of dissolution Cs C and is essentially


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During the early phase of dissolution, Cs C and is essentially

equal to saturation solubility S. Surface area A and volume V

can be held constant. Under these conditions and at constant

temperature and agitation, Equation reduces to-

Dissolution rate as expressed in Equation is termed the intrinsic

dissolution rate and is characteristic of each solid compound in

a given solvent under fixed hydrodynamic conditions.

The intrinsic dissolution rate in a fixed volume of solvent is

generally expressed as mg dissolved/cm2/min.


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Determination

Compounds with intrinsic dissolution rates greater than 1

mg min-1 cm-2 are not likely to present dissolution rate-limited absorption problems.

Those with rates below 0.1 mg min-1 cm-2 are suspect and

usually exhibit dissolution rate-limited absorption.

For compounds with rates between 0.1 and 1. 0 mg min-1

cm-2, usually more information is needed before making

any prediction.

D i i


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Determination

The determination of the intrinsic dissolution rate can be

accomplished best using the rotating-disk method.


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PARAMETERS AFFECTING

ABSORPTION


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The absorption of drugs administered orally as solids consists

of two consecutive processes:

the process of dissolution,

transport of the dissolved material across gastrointestinal

membranes into the systemic circulation.

For relatively insoluble compounds, the rate-determining stepin the overall absorption process is generally the rate of

dissolution.

For relatively soluble compounds the rate of permeationacross biological membranes is the rate-determining step.


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Physicochemical properties that are related to the process of

absorption are

i. Solubility and the dissolution rate

ii. Partition coefficient, which reflects the relative

aqueous and lipid solubilities of a material,

iii. Ionization behavior.

iv. Permeation behavior, in vitro transport measurementsusing biological membranes are extremely useful.

The rate of dissolution can be altered via physical intervention. The

rate of permeation, on the other hand is dependent on size,relative aqueous and lipid solubilities, and ionic charge of thesolute molecules. These properties can be altered. in the majorityof cases, only through molecular modification.

Significance


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Significance

The characterization of the permeation behavior of a new drugmust be performed at an early stage of drug development-

primarily to help avoid mistaken efforts to improve its

absorption by improving dissolution, when in reality the

absorption is permeability-limited.

Permeability studies are of even greater importance when

analogs of the compound having similar pharmacological

attributes are available. Permeability studies then would aid in

the selection of the compound with the greatest absorptionpotential.


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Partition Coefficient or

Distribution coefficient

Gastrointestinal membranes are largely lipoidal in character.


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Gastrointestinal membranes are largely lipoidal in character.

An indication of the relative lipid solubility, however, can be

obtained by determining how a drug substance distributesitself between water and an immiscible organic solvent.

When a solute is added to two immiscible liquids that are in

contact with each other, it will distribute itself between the

two phases in a fixed ratio. This ratio is known as thepartition coefficient or the distribution coefficient, and isessentially independent of concentration of dilute solutions

of a given solute species.

Various organic solvents such as chloroform, ether, amyl acetate,

isopropyl myristate, carbon tetrachloride, and n -octanol can be used in

the determination of the partition coefficient.

Correlation of partition coefficient with absorption:


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These data show that for a series of barbituric acids with comparable

ionization characteristics, there is a good rank-order correlation between

the amounts absorbed from the rat colon and the chloroform / water

partition coefficients of the un-ionized forms. (Schanker)


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The correlation can also

depend on the choice oforganic solvent used.

It can be seen here that

for some barbiturates, the

relationship betweenpartition coefficients and

absorption in vivo is very

much dependent on the

nature of the organicphase used.

Determination of partition coefficient:


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p

A. Both the aqueous and the organic phases are presaturatedwith respect to each other. The drug is then dissolved in

either the aqueous or the organic phase, and the known

volumes of the two phases are equilibrated by shaking.

The phases are separated by standing or via centrifugation.

The concentration of the solute is generally determined in

one of the phases and the concentration in the other is

obtained by difference.

Determination of partition coefficient:


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B. Another method applicable for estimation of partition coefficients

of a compound belonging to a family of structurally similar

compounds utilizes a reverse phase HPLC system.

Here, logarithmic value of partition coefficient (log P) is

correlated linearly with the logarithmic value of HPLC capacity

factor (log k) according to the following relationship:


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The advantages of the chromatographic method are that it

(a) is fast,(b) uses micro samples, and

(c) is suitable for substances containing impurities and for

mixtures.

However, this method requires a reference log P versus

log k graph for structurally similar compounds.


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Ionization Constant

Many drugs are either weakly acidic or basic compounds and,


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Many drugs are either weakly acidic or basic compounds and,

in solution, depending on the pH value, exist as ionized or un-

ionized species.

The un-ionized species are more lipid-soluble and hence

more readily absorbed. The gastrointestinal absorption of

weakly acidic or basic drugs is thus related to the fraction of

the drug in solution that is un-ionized. The conditions that

suppress ionization favor absorption.

pH partition theory

pH at the site of absorption,Ionization constant, and

Lipid solubility of the un-ionized species.

Henderson-Hasselbalch equations & ionization constant:


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The relative concentrations of un-ionized and ionized forms of

a weakly acidic or basic drug in a solution at a given pH can

be readily calculated using the Henderson-Hasselbalch

equations:

Here, pKa - the negative logarithm of the acidic ionization

constant.

It is apparent from the Henderson-Hasselbalch equations


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that

For acidic compounds the relative concentration of theun-ionized form would increase with a decrease in the

pH of a solution. whereas the converse would hold for

basic compounds.

The stomach contents are acidic. ranging in pH from 1 to3, whereas the pH of intestinal fluids ranges from 5 to 8.

Hence, weakly acidic but not basic drugs would be

preferentially absorbed from the stomach,

The intestine is the primary site for the absorption of

bases.


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The dependency of absorption of weakly acidic and basic drugson the pH of intestinal solution


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p

Absorption of a number of acidic and basic compounds from the

rat colon, observed that

weakly acidic compoundspKa < 4.3 - absorbed relatively rapidly;

pKa values ranging between 2.0 and 4.3 - absorbed more slowly; and

Strong acids (pKa > 2.4) hardly absorbed.

For basespKa values smaller than 8.5 were absorbed relatively rapidly; pKa between 9

and 12 were absorbed more slowly; and

Completely ionized quaternary ammonium compounds were not absorbed.

Knowledge of the pKa of a drug is thus very useful in

determining the most likely site of absorption of acidic and basic

drugs.


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Permeation Across Biological

Membranes


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In vitro experiments using biological membranes

These techniques measure the rate of permeation of drugs

in solution across the intestine of mouse or rat and provide

very useful information pertaining to the absorptioncharacteristics of drugs.


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A. Solid-State Stability

STABILITY

Solid-state stability refers to -

Physical stability


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Physical stabilityChemical stability

In general, pharmaceutical solids degrade as a result ofsolvolysis,oxidation, photolysis, and pyrolysis.

For example

1. Esters, Iactams , and, to a lesser extent, amides are susceptible

to solvolytic breakdown.2. The presence of unsaturation or of electron-rich centers makes

the molecule susceptible to free radical- mediated or photo

catalyzed oxidation.

3. Strained rings are more prone to pyrolysis.

With a number of possibilities suggested, it is possible to design the

proper stress conditions to challenge the suspected weaknesses.

Factors


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The stability study should be designed to identify the factors that

cause degradation of the drug.

The most common factors that cause solid -state reactions are

heat, light, oxygen. and, most importantly, moisture.

Most often there is considerable interplay among these factors -

heat and moisture can cause a material with a tendency to react

with oxygen to do so more rapidly; conversely, the presence of

moisture can render a substance more heat-labile.

In the conduct of stability studies, where stability is influenced bymore than one factor, it is advisable to study one factor at a time,

holding others constant.

Accelerated stability studies


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Accelerated stability studies

Solid-state reactions, in general. are slow, and it is customary to

use stress conditions in the investigation of stability. The dataobtained under stress conditions are then extrapolated to make a

predication of stability under appropriate storage conditions.

Limitations:

I. This approach is not always straightforward, and due care

must be exerted in the interpretation of the data.

II. Degradative pathways observed at elevated temperaturesmay not be operant at lower temperatures.

Limitations:


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Some ergot alkaloids degrade completely within a year when

stored at temperatures above 45C; however, the rate is less

than 1% per year below 35C.Above 65% relative humidity the form of chlortetracycline HCl

transforms into the form. The rate of transformation increasing

with the increased aqueous tension. At or below 65% relative

humidity, however, no transformation is observed.

Utility:I. Extremely useful in providing an early and a rapid prognosis of

stability.

II. Such studies are also used to force formation of degradants in

amounts sufficient for isolation and characterization.

III. This information can then be used not only in the understanding

of reaction kinetics but, if necessary, to set limits on amounts of

degradants.


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The elevated temperatures most commonly used are 30, 40, 50,and 60C in conjunction with the ambient humidity Occasionally


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and 60C-in conjunction with the ambient humidity. Occasionally,higher temperatures are used.

Study procedure:A. The samples stored at the highest temperature should be

examined for physical and chemical changes at frequent

intervals, and any change. when compared to an appropriate

control (usually a sample stored at 5 or -20C), should be

noted. If a substantial change is seen, samples stored at

lower temperatures are examined. If no change is seen after

30 days at 60C. the stability prognosis is excellent.

B. Evidence must be obtained by monitoring the samples stored

at lower temperatures for longer durations. samples stored atroom temperature and at 5C may be followed for as long as

6 months. The data obtained at elevated temperatures may

be extrapolated using the Arrhenius treatment to determine

the degradation rate at a lower temperature.


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Degradation of vitamin C at 50, 60, and 70C. The elevated-temperaturedegradation data plotted in the Arrhenius fashion, where the logarithm of

the apparent rate constant is plotted as a function of the reciprocal of

absolute temperature. The plot is linear and can be extrapolated to

obtain the rate constant at other temperatures.


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2. Stability Under High-Humidity Conditions


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In the presence of moisture, many drug substances hydrolyze,

react with other excipients, or oxidize.

Method:

These reactions can be accelerated by exposing the solid drug to

different relative humidity conditions.

Controlled humidity environments can be readily obtained using

laboratory desiccators containing saturated solutions of various

salts. The closed desiccators in turn are placed in an oven to

provide a constant temperature.

Decarboxylation of paminosalicylic acid show a dependence on

th bi t i t Th d t l th t th th d t


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the ambient moisture. These data reveal that the zeroth-order rate

constant as well as the lag time depend on the aqueous tension.


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Preformulation data of this nature are useful-

I. In determining if the material should be protected and storedin a controlled low-humidity environment, or if the use of an

aqueous-based granulation system should be avoided.

II. They may also caution against the use of excipients that

absorb moisture significantly.


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3. Photolytic Stability


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Many drug substances fade or darken on exposure to light.

Usually the extent of degradation is small and limited to theexposed surface area.

It presents an aesthetic problem-which can be readily controlled

by using amber glass or an opaque container, or by

incorporating a dye in the product to mask the discoloration.Obviously. the dye used for this purpose would be sufficiently

photostable.

Method:


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Exposure of the drug substance to 400 and 900 footcandles (fc)

of illumination for 4- and 2-week periods respectively. is

adequate to provide some idea of photosensitivity.

Over these periods, the samples should be examined frequently

for change in appearance and for chemical loss and they should

be compared to samples stored under the same conditions butprotected from light.

The change in appearance may be recorded visually or

quantitated by instruments specially designed for comparing

colors or by diffuse reflectance spectroscopy.

For example


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A sample of cicloprofen became intensely yellow after 5 days

under 900 fc of light. The progress of discoloration could bereadily followed using diffuse reflectance spectroscopy. Analysis

of the exposed sample showed less than 2% loss in cicloprofen.

The degradation products were determined to be safe.

Discoloration in this instance was an aesthetic problem only.


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4. Stability to Oxidation

The sensitivity of each new drug entity to atmospheric oxygen must

be evaluated to establish


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be evaluated to establish

if the final product should be packaged under inert atmospheric

conditions and

if it should contain an antioxidant.

Method:Sensitivity to oxidation of a solid drug can be ascertained by

investigating its stability in an atmosphere of high oxygen tension.

Usually a 40% oxygen atmosphere allows for a rapid

evaluation.

Some consideration should be given as to how the sample isexposed to this atmosphere. A powder bed should be used with an

adequate volume of head space to ensure that the system is not

oxygen-limited. Results should be compared against those

obtained under inert or ambient atmospheres.

Method: ...


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Desiccators equipped with three-way stopcocks are useful for

these studies. Samples are placed in a desiccator that is alternately

evacuated and flooded with the desired atmosphere. The processis repeated three to four times to assure essentially 100% of the

desired atmosphere.

This study can often be combined with an elevated temperature

study, in that the samples under a 40% oxygen atmosphere can

also be heated.


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B. Compatibility Studies:

Stability in the Presence of Excipients


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A typical tablet contains binders, disintegrants, lubricants, and

fillers.

In the tablet dosage form the drug is in intimate contact with one or

more excipients; the latter could affect the stability of the drug.

Knowledge of drug-excipient interactions is therefore very useful to

the formulator in selecting appropriate excipients. This informationmay already be in existence for known drugs. Fornew drugs or

new excipents, the preformulation scientist must generate the

needed information.

Method:

A Compatibility screening for a new drug must consider two or


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A. Compatibility screening for a new drug must consider two or

more excipients from each class.

The ratio of drug to excipient used in these tests: It should beconsistent with the ratio most likely to be encountered in the final

tablet, and will depend on the nature of the excipient and the size

and potency of the tablet.

Recommended drug/excipient ratios of 20: 1 and 1: 5 by weight for

lubricants and other excipients, respectively.

B. Often the interaction is accentuated for easier detection by

compressing or granulating the drug-excipients mixture with wateror another solvent.


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Importance:A ill t ti f i t f


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An illustration of importance of

drug/excipient ratio on the drug

stability is presented in Figure.These data show that the stability of

captopril-a drug prone to oxidative

degradation-in mixtures with lactose

monohydrate was inversely

proportional to its concentration.

Similar observations were made for stability in mixtures withmicrocrystalline celluslose and starch.

Techniques for determination:


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The three techniques commonly employed in drug-excipient

compatibility screening are chromatographic techniques using

HPLC or TLC,

Differential thermal analysis, and

Diffuse reflectance spectroscopy.


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C. Solution Phase Stability

These studies are necessary to assure that the drug substance


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(intended to be formulated into a solid dosage form such as a

tablet ) does not degrade intolerably when exposed to

gastrointestinal fluids.

For labile drugs, the information is useful in selection of

granulation solvent and drying conditions. Thus, the stability of

the dissolved drug in buffers ranging from pH 1 to 8 should be

investigated.

A. If the drug is observed to degrade rapidly in acidic

solutions, a less soluble or less susceptible chemical form

may show increased relative bioavailability. Alternately, an

enteric dosage form may be recommended for such a

compound.

Example:


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Example:

Erythromycin is rapidly inactivated in the acidic environment

of the stomach. The use of relatively insoluble propionyl

erythromycin lauryl sulfate (erythromycin estolate) is

recommended to circumvent this problem.

Other salts, such as stearates and salts of carboxylic acidsare less satisfactory because hydrochloric acid of the gastric

juice readily displaces the relatively weakly acidic anions and

dissolves the antibiotic as the soluble hydrochloride salt. The

estolate, being a salt of a very strong acid, lauryl sulfuric

acid, is not affected by the hydrochloric acid. It remainsundissolved and potent even after prolonged exposure to

gastric acid.

B. The availability of pH-rate profile data is sometimes useful in

predicting the solid state stability of salt forms or the stability of


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predicting the solid -state stability of salt forms or the stability of

a drug in the presence of acidic and basic excipients.

The pH -rate profile for ampicillin, a broad-spectrum -lactam antibiotic shows that-

The antibiotic is significantly less stable in both acidic and basic

solutions.Both the hydrochloride and the sodium salt of ampicillin are

significantly less stable as solids, compared to free ampicillin,

when exposed to moisture.

Compounds containing sulfhydryl groups are susceptible tooxidation in the presence of moisture. These compounds are

more stable under acidic conditions.

If a drug substance is judged to be physically or chemically

unstable when exposed to moisture a direct compression or


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unstable when exposed to moisture. a direct-compression or

non-aqueous solvent granulation procedure is to be

recommended for the preparation of tablets.

Before using a nonaqueous solvent for this purpose, stability of

the drug in the solvent must be ascertained-since many

reactions that occur in aqueous solutions may take place in

organic solvents.

Reactions in solution proceed considerably more rapidly than

the corresponding solid state reactions. Degradation in solution

thus offers a rapid method for the generation of degradation

products. The latter are often needed for the purposes ofidentification and synthesis (to study their toxicity where

appropriate) and the development of analytical methods.

9. Preformulation Testing

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