ejbps, 2015, Volume 2, Issue 2, 518-532. Research Article SJIF Impact Factor 2.

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Ramarao et al. European

EuropeanJournal of Biomedical
Journal of Biomedical ISSN 2349-8870
and Pharmaceutical Sciences
Volume: 2
AND Issue: 2
Pharmaceutical sciences 518-532
http://www.ejbps.com Year: 2015

IMPORTANCE OF PHARMACEUTICAL PREFORMULATION IN

PHARMACEUTICAL TECHNOLOGY

Ch.Taraka Ramarao*1, K.Girish Kumar2, G .Sandeep Kumar2, D.Tejeswi2,

B. Prasanna2, N.Y.Reddy2, P.Keerthi2, V.Appalanaidu2 and V.Sravani2

1. Assistant. Professor, Department of Pharmaceutical Technology, Sri Venkateswara

College of Pharmacy, Etchrela, Srikakulam, Andhra Pradesh- 532410.
2. 4/4 B.Pharm, Sri Venkateswara College of Pharmacy, Etchrela, Srikakulam, Andhra
Pradesh- 532410.
Article Received on 01/03/2015 Article Revised on 25/03/2015 Article Accepted on 19/04/2015

ABSTRACT
*Correspondence for
In recent years, there has been a significant increase in pressure on
Author
Ch.Taraka Ramarao pharmaceutical companies to discover and develop new medicines ever
Assistant. Professor, faster to replace those coming off patent and to counter generic
Department of manufacturer competition. It is important that the reader is aware of the
Pharmaceutical Technology,
nature of pharmaceutical research and development (R&D) to
Sri Venkateswara College of
appreciate the importance of preformulation and formulation in the
Pharmacy, Etchrela,
Srikakulam, Andhra overall process. After first-time-in-human (FTIH) studies in early
Pradesh- 532410. development, if the compound progresses into full development, a
more complete physicochemical characterization of the chosen
compound, with particular emphasis on the dosage form, should be carried out, thus allowing
a rational, stable, and bioavailable formulation to be progressed through to launch. Generally,
drug absorption from the GI tract requires that the drug is brought into solution in the GI
fluids and that it is capable of crossing the intestinal membrane into the systemic circulation.
It has therefore been suggested that the drug must be in its molecular form before it can be
absorbed. Approaches to lead generation during exploratory research often depend on how
much is already known about the therapeutic target under consideration. The objective of the
review is prior to the development of tablets, capsules and injectables dosage forms, it is
essential that certain fundamental physical and chemical properties of the drug molecule and
other derived properties of the drug powder are determined. This information dictates many

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of the subsequent events and approaches in formulation development. This first learning
phase is known as preformulation.

KEYWORDS: Solubility, Dissolution rate, melting point, flow properties, stability studies.

INTRODUCTION
Almost all new drugs are marketed as tablets, capsules. Although only a few are marketed as
an injection (25% of those marketed as tablets) the intravenous route is always required
during early toxicity, metabolic, bioavailability and clinical studies to provide a precise drug
and dose deposition. Prior to the development of these three major dosage forms, it is
essential that certain fundamental physical and chemical properties of the drug molecule and
other derived properties of the drug powder are determined. This information dictates many
of the subsequent events and approaches in formulation development. This first learning
phase is known as preformutation.[19]

Objective of Preformulation
1. To establish the necessary physico chemical properties of newdrug substances
2. To determine its kinetic rate profiles
3. To establish its physical characterstics
4. To establish its compatibility with common excipients
A recommended list of the information required in preformulation is shown in Table.1.
Table.1
Preformulation drug characterization
Test Method/function/characterization
1. Spectroscopy Simple UV assay
2. Solubility Phase solubility, purity
a. aqueous Intrinsic solubility, pH effects
b. pKa Solubility control, salt formation
c. salts Solubility, hygroscopicity, stability
d. solvents Vehicles, extraction
e. partition coefficient Lipophilicity, structure activity
f. dissolution Biopharmaceutics
3. Melting point DSC - polymorphism, hydrates, solvates
4. Assay development UV, TLC, HPLC
Thermal, hydrolysis, oxidation,
5. Stability (in solution and solid state)
photolysis, metal ions, pH.
6. Microscopy Morphology, particle size
7. Powder flow Tablet and capsule formulation
a. bulk density angle of repose
8. Compression properties Tablet and capsule formation
9. Excipient compatibility Excipient choice

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1. SPECTROSCOPY

The first step in preformulation is to establish a simple analytical method. Most drugs
absorb light in the ultraviolet wavelengths (190-390 run) as they are generally aromatic
and contain double bonds. The acidic or basic nature of the molecule can be predicted
from functional groups.[1]

Using the UV spectrum of the drug, it is possible to choose an analytical wavelength (λ
max) suitable to quantify the amount of drug in a particular solution.

Excitation of the molecule in solution causes a loss in light energy, and the net change
from the intensity of the incident light (I O) and the transmitted light (I) can be measured.

Their greater training and knowledge in analysis will assist in the identification of
suitable stability-indicating assays by high-performance liquid chromatography (HPLC).
Independent of this pharmaceutical profiling analysts will generate data to confirm
structure and purity, and this should be used to complement and confirm pharmaceuticals.

Attribute Test
Nuclear magnetic resonance (NMR)
Infra red spectroscopy (IR)
Ultraviolet spectroscopy (UV)
1.Identity
Thin-layer chromatography (TLC)
Differential scanning calorimetry (DSC)
Optical rotation, where applicable
Moisture (water and solvents)
Inorganic elements
2. Purity Heavy metals
Organic impurities
Differential scanning calorimetry (DSC)
Titration
3. Assay Ultraviolet spectroscopy (UV)
High-performance liquid chromatography (HPLC)
Appearance
Odour
4. Quality Solution colour
pH of slurry (saturated solution)
Melting point
2. SOLUBILITY
a. Aqueous solubility
 The availability of a drug is always limited and the preformulation scientist may only
have 50 mg.
 Kaplan suggested that unless a compound has an aqueous solubility in excess of 1% (10
mg/mL) over the pH range 1-7 at 37°C, potential bioabsorption problems may occur.[2]

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 If the intrinsic dissolution rate was greater than 1 mg cnr2 mkr1 then absorption was
unimpeded. Dissolution rates less than 0.1 mg /cm2 /min were likely to give dissolution
rate-limited absorption. This tenfold difference in dissolution rate translates to a lower
limit for solubility of 1 mg /mL.
 A solubility of less than 1 mg/ mL indicates the need for a salt, particularly if the drug
will be formulated as a tablet or capsule. In the range 1-10 mg/ mL serious consideration
should be given to salt formation.
 When the solubility of the drug cannot be manipulated in this way (neutral molecules,
glycosides, steroids, alcohols, or where the pKa is less than 3 for acid or greater than 10
for an base) then liquid filling in soft or hard gelatin capsules may be necessary.

b. Intrinsic solubility (C0)

 When the purity of the drug sample can be assured, the solubility value obtained in acid
for a weak acid or alkali for a weak base can be assumed to be the intrinsic solubility
(C0), ie. the fundamental solubility when completely unionized.
 The solubility should ideally be measured at two temperatures:
1. 4°C to ensure physical stability and extend short-term storage and chemical stability until
more definitive data are available. The maximum density of water occurs at 4°C.This
leads to a minimum aqueous solubility.
2. 37°C to support biopharmaceutical evaluation

c. pKa from solubility data[3]

 75% of all drugs are weak bases; 20% are weak acids and only 5% are non-ionic,
amphoteric or alcohols
 It is therefore appropriate to consider the Henderson-Hasselbalch equations for weak
bases and acids.
 For weak bases: pH = pKa+ log (unionized/ionized)
 For weak acids pH = pKa+ log (ionized/unionized)
 Equations can be used:
1. to determine pKa by following changes in solubility
2. to predict solubility at any pH, provided that the intrinsic solubility (C 0) and pKa are
known
3. to facilitate the selection of suitable salt-forming compounds and predict the solubility and
pH properties of the salts

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 To obtain precise pKa values by potentiometry, spectroscopy and conductivity.

d. Salts
 In some cases, salts prepared from strong acids or bases are freely soluble but very
hygroscopic. This does lead to instability in tablet or capsule formulations, as some drug
will dissolve in its own adsorbed films of moisture.[4]
 Salts require for Basic drugs such as Hydrochloride, Sulphate, Mesylate, Maleate,
Phosphate, Salicylate, Tartrate, Lactate, Citrate. Succinate, Acetate.
 Salts require for acidic drugs such as Potassium, Sodium, Lithium, Calcium, Magnesium,
Diethanolamine, Zinc, Choline, Aluminium.
 It is often better to use a weaker acid or base to form the salt, provided any solubility
requirements are met. A less soluble salt will generally be less hygroscopic and form less
acidic or basic solutions.
 Injections should ideally lie in the pH range 3-9 to prevent vessel or tissue damage and
pain at the injection site. Oral syrups should not be too acidic, to enhance palatability.
 Packaging may also be susceptible: undue alkalinity will attack glass, and hydrochloride
salts should not be used in aerosol cans as a propellant-acid reaction will corrode the
canister.
 A weak base with an intrinsic solubility greater than 1 mg/ mL will be freely soluble in
the gastrointestinal tract, especially in the stomach. However, it is usually better to
formulate with a salt, as it will control the pH of the diffusion layer.
 A weak base will have a high dissolution rate in the stomach, but as it moves down the
gastrointestinal tract the pH rises and dissolution rate falls.
 Conversely, a weak acid has minimal dissolution in the stomach but becomes more
soluble and dissolution rate increases down the gut.
 Paradoxically, as dissolution rate increases so absorption falls because the drug is ionized.
 The dissolution rate of a particular salt is usually much greater than that of the parent
drug. Sodium and potassium salts of weak acids dissolve much more rapidly than do the
parent acids.[8,17,18]
 However, the pH of the diffusion layer is higher than that of gastric fluid because of its
buffering action.
 Different salts of a drug rarely change pharmacology, but only physical properties. This
statement has been qualified to acknowledge that salts do affect the intensity of response.

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 However, the salt form does change the physiochemical properties of the drug. Changes
in dissolution rate and solubility affect the rate and extent of absorption (bioavailability),
and changes on hygroscopicity and stability influence formulation.

e. Solvents
 The first choice solvent is obviously water. However, although the drug may be freely
soluble, it may be unstable in aqueous solution.[5]
 Accordingly, water-miscible solvents are used:1. in formulations to improve solubility or
stability 2. in analysis to facilitate extraction and separation (e.g. chromatography).
 Oils are used in emulsions, topicals (creams and ointments), intramuscular injections and
liquid-fill oral preparations (soft and hard gelatin capsules) when aqueous pH and solvent
solubility and stability are unattainable.
 Aqueous methanol is widely used in HPLC and is the standard solvent in sample
extraction during analysis and stability testing.
 The most acceptablenon-aqueous solvents pharmaceutically are glycerol, propylene
glycol and ethanol. Generally for a lipophilic drug.
 Formulations rarely use pure non-aqueous solvent, particularly injections. For example,
ethanol should only be used up to 10% in an injection to prevent haemolysis and pain at
the injection site, and include isotonic salts.

f. Partition coefficient
Partition coefficient has a number of applications which are relevant to preformulation [15,16]:
1. Solubility: both aqueous and in mixed solvents 2. Drug absorption in vivo: applied to a
homologous series for structure activity relationships (SAR) 3. Partition chromatography:
choice of column (HPLC) or plate (TLC) and choice of mobile phase (eluant).

 Solvent solubility: The relative polarities of solvents can be scaled using dielectric
constant (e), solubility parameter, interfacial tension and hydrophilic-lipophilic balance
(HLB).

Methodology and structure activity prediction

Choice of non-aqueous solvent
 Many partition solvents have been used. The largest database has been generated using n-
octanol. Thesolubility parameter of octanol (8 = 10.24) lies midway in the range for drugs
(8-12), although some non-polar (8 < 7) and polar drugs (8 > 13) are encountered.

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 In the shake flask method the drug, dissolved in one of the phases, is shaken with the
other partitioning solvent for 30 minutes, allowed to stand for 5 minutes, and then the
majority of the lower aqueous phase (density of octanol = 0.8258 g mL L) is run off and
centrifuged for 60 minutes at 2000 rpm. The aqueous phase is assayed before (ΣC) and
after partitioning (Cw) [the aqueous concentration] to give K o/w = ΣC - CW)/(Cw).
 In general, polar solvents are advocated to correlate biological activity with
physicochemical properties.
 Solvents less polar than octanol, measured by water solvency, have been termed hyper
discriminating, whereas more polar solvents such as butanols and pentanols, are hypo
discriminating. This concept refers to the discriminating power of a partitioning solvent
within a homologous series.
 Octanol generally gives a range consistent with other physicochemical properties when
compared to drug absorption in the GI tract.
 Hyper discriminating solvents reflect more closely the transport across the blood-brain
barrier, whereas hypo discriminating solvents give values consistent with buccal
absorption.

g. DISSOLUTION
 solubility of a drug exceeded 10 mg mL"1 at pH <7, no bioavailability- or dissolution-
related problems were to be expected.
 Below 1 mg mL such problems were quite possible, and salt formation could improve
absorption and solubility by controlling the pH of the microenvironment independently of
the drug and dosage forms' position within the GI tract.

Intrinsic dissolution rate[20]

 When dissolution is controlled solely by diffusion the rate of diffusion is directly
proportional to the saturated concentration of the drug in solution Under these conditions
the rate constant K is defined by: k=0.62 D2/3 V1/6 ω1/2
 where v is the kinematic viscosity and ω is the angular velocity of a rotating disc of drug.
By maintaining the dissolution fluid viscosity and rotational speed of the sample constant,
the dissolution rate (dc/dt) from a constant surface area (A) will be constant and related
solely to solubility IDR= K1Cs mg/cm2/min

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 This constant rate differs from the dissolution from conventional dosage forms, which is
known as total dissolution (mg /mg), where the exposed surface area (A) is uncontrolled
as disintegration, deaggregation and dissolution proceed.
 Accordingly, the IDR is independent of formulation effects and measures the intrinsic
properties of the drug and salts as a function of dissolution media, e.g. pH, ionic strength
and counter-ions.

h. Common ion effect

 A common ion often significantly reduces the solubility of a slightly soluble electrolyte.
The 'salting out' results from the removal of water molecules as solvent owing to the
competing hydration of other ions.
 The reverse process, 'salting in', arises with larger anions, e.g. benzoate, salicylate, which
open the water structure.
 These hydrotropes increase the solubility of poorly water-soluble compounds such as
diazepam.

3. Melting point
 The melting point of a drug can be measured using three techniques:
1. Capillary melting
2. Hot stage microscopy
3. Differential scanning calorimetry or thermal analysis
 Capillary melting (the observation of melting in a capillary tube in a heated metal block)
gives information about the melting range but it is difficult to assign an accurate melting
point.
 Hot stage microscopy
This is the visual observation of melting under a microscope equipped with a heated and
lagged sample stage. It is more precise as the phase transitions (first melt, 50% melt and
completion) can be registered on a recorder as the melting proceeds, and because of the
high magnification the values are more accurate.

 Differential scanning calorimetry and thermal analysis

 DTA measures the temperature difference between the sample and a reference as a
function of temperature or time when heating at a constant rate.

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 DSC is similar to DTA, except that the instrumentmeasures the amount of energy
required to keep the sample at the same temperature as the reference, i.e. it measures the
enthalpy of transition.

a. Polymorphism
 A polymorph is a solid material with at least two different molecular arrangements that
give distinct crystal species. The highest-melting species is generally stable; other
polymorphs are metastable and convert to the stable form.
 Solubility (particularly important in suspensions and biopharmaceutically)9,10, melting
point, density, crystal shape, optical and electrical properties and vapour pressure are
often very different for each polymorph.
 Polymorphism is remarkably common, particularly within certain structural groups: 63%
of barbiturates, 67% of steroids and 40% of sulphonamides exhibit polymorphism.

Pseudo polymorphism
 It should be identified, as most polymorphs can be obtained by changing the
recrystallizing solvent. Typical solvents inducing polymorphic change are water,
methanol, ethanol, acetone, chloroform, n-propanol, isopropanol alcohol, butanol, n-
pentanol, toluene and benzene.
 The distinction between these false forms and true polymorphs can be ascertained by
observing the melting behaviour of the compound dispersed in silicone oil using hot-stage
microscopy.
 Pseudopolymorphs will evolve a gas (steam or solvent vapour), causing the oil to bubble.
True polymorphs merely melt, forming a second globular phase.[11,12]
 The temperature at which the solvent volatilizes will be close to the boiling point of the
solvent.

b. Crystal purity
 Thermal analysis has been widely used as a method of purity determination.

c. Solubility
 Melting point and solubility are related via the latent heat of fusion, which is the amount
of heat generated during melting or fusion.

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 A crystal with weak bonds has a low melting point and low heat of fusion. Conversely, a
strong crystal lattice leads to a high melting point and a high heat of fusion.

4. ASSAY DEVELOPMENT
 In order to follow drug stability, in both solution and solid phase, it is mandatory to have
suitable stability indicating assays.[13,14]
 In some cases UV spectroscopy can be used, but in general chromatography is required to
separate the drug from its degradation products and any excipients.

5. DRUG AND PRODUCT STABILITY

 commercial pharmaceutical products should have a shelf-life of 3 years.[7]
 The potency should not fall below 95% under the recommended storage conditions and
the product should still look and perform as it did when first manufactured.

a. Temperature
 Typically a 10°C increase in temperature can produce a 2-5-fold increase in decay. Often
the increase in reaction rate with temperature follows an Arrhenius-type relationship: a
plot of the log of the rate of reaction against the reciprocal of absolute temperature yields
a straight line.
 The reaction rate can then be calculated at any temperature and allows a prediction of
shelf-life at room temperature by extrapolation.
 This assumption forms the basis of accelerated stability tests.

d. Order of reaction
 The most common is the half-life, the time at which the concentration has halved • The
shelf-life of a product can be likewise expressed as t 95% (i.e. the time for 5% loss) etc.

e. Hydrolysis
 Hydrolytic reactions involve nucleophilic attack of labile bonds, e.g. lactam > ester >
amide > imide, by water on the drug in solution, and are first order.
 A number of conditions catalyse the breakdown: The presence of OH, presence of H3O,
presence of divalent metal ions, Ionic hydrolysis (protolysis) is quicker than molecular,
Heat, Light,Solution polarity and ionic strength, High drug concentrations.

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f. Influence of pH
 The degradation of most drugs is catalysed by extremes of pH, i.e. high [H3O+] and
[OH], and many drugs are most stable between pH 4 and 8.
 Where maximum stability dictates wider values, it is important for injections that there is
low buffer capacity to prevent unnecessary challenge to the homeostatic pH (7.4) of
blood.
 In some cases, therefore, the inclusion of a water-miscible solvent in the formulation will
increase stability by: Suppressing ionization, Reducing the extreme of pH required to
achieve solubility, Reducing water activity by reducing the polarity of the solvent, e.g.
20% propylene glycol in chlordiazepoxide HC1 injection.

g. Solvolysis
 Where the reacting solvent is not water, then breakdown is termed solvolysis.
 In general, if a compound produces degradation products which are more polar then the
addition of a less polar solvent will stabilize the formulation.
 If the degradation products are less polar, then the vehicle should be more polar to
improve stability.

F. Oxidation
 Oxidation is controlled by the environment, i.e. light, trace metals, oxygen and oxidizing
agents
 However, most antioxidants function by providing electrons or labile H+, which will be
accepted by any free radical to terminate the chain reaction

G. Chelating agents
 Chelating agents are capable of forming more than one bond. For example, ethylene
diamine is bidentate, ethylene diamine tetra-acetic acid (EDTA) is hexadentate (six),
which makes it particularly effective as a pharmaceutical chelating agent.

h. Photolysis

The energy associated with this radiation increases as wavelength decreases, so that the
energy of UV visible is greater than that of IR and is independent of temperature which
can cause decomposition, be retained or transferred, be converted to heat, result in light
emission at a new wavelength (fluorescence, phosphorescence)7

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 Thus photolysis is prevented by suitable packaging: low actinic amber glass bottles,
cardboard outers and aluminium foil overwraps and blisters

i. Solid-state stability
 In all solid dose formulations there will be some free moisture (contributed by excipients
as well as the drug), and certainly in tablets a significant percentage, typically 2% w/w, is
required to facilitate good compression

j. Hygroscopicity
 A substance that absorbs sufficient moisture from the atmosphere to dissolve itself is
deliquescent. A substance that loses water to form a lower hydrate or becomes anhydrous
is termed efflorescent
 Good packaging will accommodate moisture challenge, e.g. glass bottles, foil blisters and
dessicant.
 However, preformulation studies on the drug and potential excipient combinations should
provide the basis for more robust formulations and a wider, more flexible and cheaper
choice of pack, while still reducing significantly any hydrolytic instability due to
absorbed free moisture.

6. MICROSCOPY
 Two major applications in pharmaceutical preformulation: Basic crystallography, to
determine crystal morphology (structure and habit), polymorphism and solvates, Particle
size analysis.
 Most pharmaceutical powders have crystals in the range 0.5-300 µ. However, the
distributions are often smaller, typically 0.5-50 µ, to ensure good blend homogeneity and
rapid dissolution. These are
 The major reasons for particle size control. There are numerous methods of particle
sizing.
 Sieving is usually unsuitable during preformulation owing to the lack of bulk material.
The simplest method for small quantities is the microscope.
 The Coulter Counter and laser light scattering are widely used for routine bulk analysis
and research.

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7. POWDER FLOW PROPERTIES

 When limited amounts of drug are available this can be evaluated by measurements of
bulk density and angle of repose.
 These are extremely useful derived parameters to assess the impact of changes in drug
powder properties as new batches become available.

8. COMPRESSION PROPERTIES
 When the dose is less than 50 mg, tablets can usually be prepared by direct compression
with the addition of modern direct compression bases. At higher doses the preferred
method would be wet massing.
 Nonetheless, information on the compression properties of the pure drug is extremely
useful
 Although it is true that the tableted material should be plastic, i.e. capable of permanent
deformation, it should also exhibit a degree of brittleness (fragmentation).
 Thus if the drug dose is high and it behaves plastically, the chosen excipients should
fragment, e.g. lactose, calcium phosphate.
 If the drug is brittle or elastic, the excipients should be plastic, i.e. microcrystalline
cellulose, or plastic binders should be used in wet massing.
 The compression properties elasticity, plasticity, fragmentation and punch filming
propensity

9. EXCIPIENT COMPATIBILITY
 The successful formulation of a stable and effective solid dosage form depends on the
careful selection of the excipients that are added to facilitate administration, promote the
consistent release and bioavailability of the drug and protect it from degradation.
 The preformulation screening of drug-excipient interactions requires 5 mg of drug, in a
50% mixture with the excipient, to maximize the likelihood of observing an interaction.
 Mixtures should be examined under nitrogen to eliminate oxidative and pyrrolytic effects
at a standard heating rate (2, 5 or 10°C /min) on the DSC apparatus, over a temperature
range which will encompass any thermal changes due to both the drug and excipient.

CONCLUSIONS
 Preformulation studies have a significant part to play in anticipating formulation
problems and identifying logical paths in both liquid and solid dosage form technology.

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