Bharate & Vishwakarma - Expert Opin Drug Del 2013, 10 (9) 1239-1257

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Impact of preformulation on drug development

Article in Expert Opinion on Drug Delivery March 2013
DOI: 10.1517/17425247.2013.783563 Source: PubMed
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Review
Impact of preformulation on
drug development
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Sonali S Bharate & Ram A Vishwakarma

1.
Introduction
Indian Institute of Integrative Medicine (CSIR), Jammu, India
2.
Salt form selection and its

stability
3.
Polymorphic phase transitions
4.
Crystal habit and druggability
5.
Chirality
6.
Bulk properties (particle size
Introduction: Preformulation assists scientists in screening lead candidates

based on their physicochemical and biopharmaceutical properties. This data
is useful for selection of new chemical entities (NCEs) for preclinical efficacy/
toxicity studies which is a major section under investigational new drug application. A strong collaboration between discovery and formulation group is
essential for selecting right NCEs in order to reduce attrition rate in the late
stage development.
Areas covered: This article describes the significance of preformulation
research in drug discovery and development. Various crucial preformulation
parameters with case studies have been discussed.
Expert opinion: Physicochemical and biopharmaceutical characterization of
NCEs is a decisive parameter during product development. Early prediction
of these properties helps in selecting suitable physical form (salt, polymorph,
etc.) of the candidate. Based on pharmacokinetic and efficacy/toxicity studies,
suitable formulation for Phase I clinical studies can be developed. Overall
these activities contribute in streamlining efficacy/toxicology evaluation,
allowing pharmacologically effective and developable molecules to reach
the clinic and eventually to the market. In this review, the magnitude of
understanding preformulation properties of NCEs and their utility in product
development has been elaborated with case studies.
and size distribution, flow,

dissolution, etc.)
7.
Hygroscopicity
8.
Drug stability
9.
Drug solubility
10.
Physical incompatibilities
11.
Biopharmaceutical
aspects -- absorption,
distribution, metabolism and
excretion
12.
Preformulation and IND

approval
13.
Conclusion
14.
Expert opinion
Keywords: drug development, investigational new drug, preformulation, product recall

Expert Opin. Drug Deliv. (2013) 10(9):1239-1257
1.
Introduction
Preformulation studies (physicochemical and biopharmaceutical properties) play a

significant role in drug discovery and development programs as they provide valuable information about druggability during lead identification and optimization.
The role of preformulation data means different things to different groups in the
discovery and development phases. For chemistry team, preformulation testing
provides clues to optimize the chemical structure with respect to solubility, permeability and stability [1,2]. For a biology group, preformulation information (permeability, solubility and stability) is useful to decide optimal drug exposure for
pharmacokinetic and toxicological studies. The analytical team gets feedback from
the preformulation group on developing stability-indicating assays and setting drug
specifications. After lead selection, as a molecule moves further toward the development phase, preformulation data provides guidance to bulk manufacturing, formulation development and clinical evaluation protocols [3]. The bulk manufacturing team
uses data generated from preformulation studies on salt selection, purity of the polymorph and particle size specifications. The formulation team utilizes maximum data
from preformulation testing to design an appropriate dosage form. Physicochemical
properties are used for improving drug solubility, permeability and stability, selecting
appropriate excipients and processing conditions to design and evaluate the final dosage form. The clinical evaluation team utilizes preformulation data along with data
from preclinical animal studies to understand the pharmacokinetics of the drug in
10.1517/17425247.2013.783563 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593
All rights reserved: reproduction in whole or in part not permitted
1239
S. S. Bharate & R. A. Vishwakarma
Article highlights.
.
Preformulation research helps in selection of NCEs for

further development cycles and is a major component of
the CMC section of IND application.
Significance of preformulation properties of APIs in drug
discovery and development has been exemplified with
case studies wherein preformulation studies helped in
product development. Case studies of product recall due
to inadequate preformulation data are also discussed.
Physicochemical characterization of chemical moieties at
an early stage of development will reduce development
costs and timelines.
Negligence toward assessment of any of the
preformulation parameters may lead to a significant
impact on total development activities.
This box summarizes key points contained in the article.
humans through the maximum absorbed dose and the biopharmaceutics classification system (BCS) paradigms. Therefore, a
strong preformulation team in the drug discovery setting is critical for optimizing the pharmaceutical properties of a drug.
This can considerably reduce attrition rate, time and cost of
developing a new drug [4-7]. An alternative approach would be
to have quick proof of concept for first-time-in-man studies to
make a decision on the drug candidate. This early proof of
concept is an alternative view for rapid, slimmed down development both in terms of cost and time.
It has been shown that inadequate preformulation data is
one of the reasons for product recalls. The information
required on preformulation will, to a certain extent, be dictated by the final product, the proposed route of administration and the development plan. A schematic overview of
preformulation characteristics is depicted in Figure 1.
An extensive number of research papers have been published on different techniques and protocols for estimation
of preformulation parameters [8], as well as there are several
reviews [9-11] on the theoretical aspects of preformulation.
Szunyogh et al. [10] reviewed (written in Hungarian language)
the importance of decreased particle size in preformulation.
Hageman [9] has discussed the assessment of key physicochemical properties and how they are implicated in both discovery enablement and in final product developability of
selected candidate. Ashizawa [11] reviewed (in Japanese language) the importance of physicochemical profiling and preformulation studies at the drug discovery stage. However,
there is no review available where the significance of individual preformulation parameters in product development is
elaborated using case studies of drug candidates. Furthermore,
a critical analysis of preformulation-related product recalls is
missing in earlier reviews. The present review provides a critical account on how understanding of chemical and pharmaceutical properties of medicinal chemistry leads plays a vital
role in product development. This has been elaborated using
case studies of drug candidates wherein preformulation data
1240
proved to be crucial in the drugs preclinical/clinical development. Additionally, case studies of product recalls have been
discussed wherein some additional preformulation data would
have avoided these withdrawals. Preformulation requisites and
regulatory aspects of preformulation for investigational new
drug (IND) applications have also been discussed. The chemical structures of drugs (1 -- 28) discussed in the following
sections are shown in Figure 2.
2.
Salt form selection and its stability
The chemical, biological, physical and economic characteristics of drug candidates can be manipulated by converting
them to a salt form. Pharmaceutical chemists and formulation
scientists modify these characteristics by selecting an appropriate salt form of a drug substance. This permits development
of dosage forms with good bioavailability, manufacturability
and stability along with patients acceptance. Salts are most
frequently employed for altering aqueous solubility; however,
selected salt forms also influence a range of other properties
such as melting point, chemical stability, hygroscopicity, solution pH, dissolution rate, crystal form and mechanical properties [12,13]. Pharmaceutical salts frequently exist as hydrates,
which create difficulties during formulation development,
particularly in wet granulation. It often becomes difficult to
monitor and control the anhydrate/hydrate form during the
wet mixing, fluid bed drying and aqueous film coating processes. This factor has led to the deselection of a particular
salt form in further development process many times [14,15].
During the drug development process, discovery of new
crystal forms offers an opportunity to select an optimal form
of a drug candidate [16]. Cocrystals have also been utilized
for modifying the physicochemical parameters of drugs.
Tsutsumi et al. [17] studied miconazole salts and cocrystals
for improving physicochemical properties. They reported
hemisuccinate as a novel cocrystal form of miconazole with
an improved dissolution rate and superior stability, making
it an alternative for nitrate salt. Pharmaceutical cocrystal strategy compliments the salt formation to enhance bioavailability
of drug product and stability [18].
The information generated from preliminary crystallization
studies is often helpful to the process chemistry group, which
investigates possible manufacturing routes for the molecule of
interest. The manufacturing route may be the same as used by
the discovery chemistry group, but it can also significantly differ. Both the process chemistry and preformulation groups
extensively collaborate for the next 12 -- 18 months in order
to ensure a viable synthetic route for the chosen salt form of
the drug candidate. A significant portion of this batch is destined for the preparation of 3 -- 4 g of each salt that were
thought to be viable from smaller-scale studies. A similarsized portion of free base/acid is also taken for comparison
purposes. The combination of individual studies undertaken
on each of these 3 -- 4 g portions varies depending on the
type(s) of dosage form ultimately required for marketing.
Expert Opin. Drug Deliv. (2013) 10(9)
Analytical
Physical
A) Molecular structure B) Chemical analysis

determination
I) Quantification II) Purity
a) Elemental
b) NMR
c) Mass spectrometry
d) IR
e) UV/Vis
a) TLC
b) HPLC
Reverse phase
Chiral
Physical analysis
f) Microscopy
a) Melting point
i) Particle shape
b) Hygroscopicity
c) Differential scanning calorimetry ii) Particle size
g) Powder
d) Thermogravimetry
i) Compaction
e) X-ray crystal determination
ii) Flow
2
a) Synthetic impurities
b) Residual solvent
c) Residual water
d) Heavy metals
e) Degradants 1
microbiology
Candidate drug
Pharmaceutical
A) Biopharmaceutical properties B) Chemical compatibility
a) Monolayer adsorption
I) Processing
b) ADME
II) Excipients
C) Regulatory stability
Physicochemical
B) Physicochemical properties
A) Chemical stability
3
I) Log P
a) Oxidation
II) pKa
b) Light
III) Solubility
c) pH
Degradants
a) Solvent
d) Temperature
b) pH
e) Solvent
c) Dissolution
Figure 1. Map of preformulation studies revolving around the candidate drug. Studies would commence in the analytical
segment and swing around to the pharmaceutical segment as the compounds development progressed. As early studies
affect later studies, the dotted pointer indicates one linkage, the determination of the UV/VIS spectrum is useful for HPLC
method development, which is influenced by synthetic impurities and degradants, which then allows degradation studies to
be conducted [8].
Occasionally, it may be necessary to undertake a pharmacokinetic evaluation of each salt in comparison with the free acid/
base. At this stage in the development process, the aim is to
quickly manufacture 50 -- 200 g of promising candidate(s)
for initial clinical evaluation. The alternative approach is to
proceed with the free base or acid form, if the drug candidate
displays efficacy in animal studies. In such cases, the extensive
process chemistry efforts can be skipped and the medicinal
chemistry synthetic route could be employed to quickly prepare free base/acid form. Formulation strategies could be
employed in order to achieve adequate exposure of the drug.
Dosage forms most commonly used for drug substances
encountered during preliminary clinical investigations are tablets/capsules, inhalation dosage forms and injections [19]. Of
the many salts synthesized, the preferred form is selected by
a pharmaceutical chemist primarily on a practical basis (raw
materials employed, ease of crystallization process and percentage yield). Other basic considerations include stability,
hygroscopicity and flowability of the resulting bulk drug.
The following representative examples illustrate how and
why selection of proper salt forms is necessary during preformulation and before going forward to product development.
The process for producing a stable chlortetracycline (1) suspension was developed at Lederle Laboratories between
1951 and 1954 [20]. Berge et al. [21] observed that hydrochloride salt was highly unstable in aqueous solution, but calcium
salt was very stable. They also reported that potassium salt of
penicillin G (2) was much less hygroscopic than sodium salt;

however, penicillin G potassium tends to have an unpleasant
metallic taste [20]. Serajuddin et al. [22] observed that hydrochloride salt of the poorly water-soluble drug REV-5901
(3, an orally effective peptidoleukotriene antagonist) is unstable due to conversion of anhydrous and monohydrate forms
to a hydrate form at > 40% relative humidity. On loss of
water at 40 -- 60 C, the hydrate form became unstable, which
was also confirmed by accelerated stability studies. However,
the basic form of REV-5901 was stable and pharmaceutically
acceptable crystalline solid. Engel et al. [23] performed a salt
selection study on LY333531 (4), a competitive reversible
inhibitor of protein kinase Cb, which was being evaluated
for treatment of diabetic complications (e.g., retinopathy
and erectile dysfunction). LY333531 as a free base has poor
aqueous solubility and thus its salt form was desired to
enhance solubility and bioavailability. Seven salts (hydrochloride, mesylate, tartrate, sulfate, succinate, acetate and phosphate) were initially crystallized and evaluated for various
physical properties such as particle size and morphology,
hygroscopicity, crystallinity and aqueous solubility in order
to find out feasibility for further development. Of the seven
salts selected, five salts (sulfate, succinate, tartrate, acetate
and phosphate) were eliminated due to poor crystallinity,
low solubility and difficulty in improving chemical purity
during preparation. The two remaining mesylate and hydrochloride salts were comprehensively analyzed for additional
1241
OH
O
OH
OH
OH
H2N
H
H
HO
OH
N
O
H
N
O
OH
Cl
NH
3 REV-5901
2 Penicillin G
1 Chlortetracycline
4 LY333531
Cl
HO
OH
Cl
OH
10 Thiamine
9 Theophylline
N
HO
O
Cl
S
HN
HO
NH HN
O
OH
H2N
S
O
15 Phenylbutazone
O
OH
HO
O
O
NH
HN
N
N
O
17 Tolbutamide 18 Hydrochlorothiazide
O
H
OH
16 Oxytetracycline
14 Rotigotine
H
OH
Cl
O
OH
OH
12 Ritonavir
H
N
N
N
O-
13 Chloramphenicol
HO
O
N
H
O
H2N
HN
8 Nelfinavir
11 Erythromycin
OH
H
N
H
N
OH
OH
N
H
Cl
O HO
O
OH
O
HO
HO
OH
N
H
OH
OH
O
NH2
H
N
O-
7 L-649923
5 Diclofenac
NH
N
N
N
NH
19 Irbesartan
OH
I
F
21 RPR 200765
HO
22 NBI 75043
H3CO
NH2
O
F
Cl
OH
HO
OH
O
O
27 Warfarin
OH
HH
OCH3
25 Combretastatin A4
HO
23 Levothyroxine
O
N
OCH3
OAc
OH
H3CO
20 Rapamune
O
O
O
O
OH
26 Flavopiridol
HN
24 Fluocinonide
NH
NH
NH2
28 Metformin
Figure 2. Chemical structures of drugs 1 -- 28 discussed in preformulation-related case studies.
1242
parameters such as polymorphism, stability, purification, filterability and relative bioavailability in dogs. Results obtained
from these efforts indicated that mesylate salt can be developed as the optimal salt form of LY333531.
Apart from salt form selection, the stability of the selected
salt is imperative. Chemical and physical aspects associated
with preparation of pharmaceutical salt are formation of
hydrates, polymorphism and amorphization. These aspects
are also important from a technological point of view, as
they affect solubility, dissolution rate and bioavailability of
drugs. Therefore, each pharmaceutical salt must undergo a
careful preformulation study in order to define experimental
conditions of its stability. Fini et al. [24] prepared salts of diclofenac (5) with various salt-forming agents in order to find the
optimally stable and soluble salt form. Diclofenac salts with
eight different cyclic aliphatic amines, such as pyrrolidine,
piperidine, morpholine, piperazine and their N-hydroxyethyl
analogs, were prepared and characterized. However, these
salts were found to possess poor aqueous solubility as compared with diclofenac sodium. Hence, each pharmaceutical
salt must undergo a careful preformulation study in order to
define its solubility and stability. Ionizable and non-ionizable
prodrugs can also be prepared to improve bioavailability of
drug candidates. However, use of free base form of the
molecule with alternative formulation strategy (nanodelivery
systems, such as nanoparticles, liposomes, nanoemulsions/
microemulsions, micelles and longer circulating half-life of
the drugs by PEGylation) is equally straight forward. Typically, the salt formation is considered as the most practical
approach to enhance bioavailability.
The maleate salt of a basic drug dibenzo-(b,f)-oxepen10-yl-methyl-methyl-prop-2-ynyl-amine (6) was found to be
more stable than free base. This selected salt was developed
for oral administration in the treatment of neurodegenerative
disorders, such as Parkinsons disease and amyotrophic lateral
sclerosis. Hard gelatin capsules of various potencies (0.25,
2.5 and 10 mg) were selected for Phase I clinical studies. After
initial clinical testing using capsules in Phases I and IIA, scientists decided to switch the dosage form from capsule to tablet
with the same potencies for the Phases IIB and III clinical
studies, for commercialization purpose. Tablets were developed with a minimal change in composition from the capsule
formulation to maintain continuity between developmental
activities of two dosage forms and to ensure that their stability
would be similar. Tablet formulations of the maleate salt of
this drug showed major loss in potency and lack of mass balance upon storage under accelerated stability testing. No such
stability problem was observed in capsules that were similar in
composition. Interestingly, the tablet was found to be stable
when it was encapsulated in a capsule shell. It was identified
that the reason behind the instability of the drug in tablets was
conversion of salt to its free base form in the microenvironment
of tablet formulation [25-27].
The free base of an orally active leukotriene D4 antagonist
L-649923 (7) was found to be highly unstable because of its
propensity to undergo intramolecular esterification to form

g-lactone. In order to avoid formation of g-lactone, formulation efforts were undertaken wherein calcium salt of drug and
tablet dosage form were chosen for formulation development.
A direct compression method was employed in tablet
manufacturing. A wet granulation process was avoided by
using excipients with low water content and adding sodium
carbonate as an alkalizing agent. This case demonstrated the
importance of considering microenvironment pH of the solid
to stabilize the drug product. Understanding degradation
mechanisms should be the basis for selecting the right salt
and developing a chemically stable solid dosage form [28,29].
The possible impurities in new chemical entities (NCEs)
are also a major concern during the drug development process. For profiling of genotoxic impurities, a rapid and convenient method for chemical analysis should be developed at an
earlier stage [30]. The recent example of the anti-HIV drug nelfinavir mesylate (Viracept), which was withdrawn from the
market has shown the importance of impurity profiling [31].
The oral formulation of nelfinavir mesylate (8) was withdrawn from the European market in mid-2007 due to elevated
levels of ethyl methanesulfonate which is a potential cancercausing contaminant. The ethyl methanesulfonate was generated as a by-product of the starting material, methane sulfonic
acid [32]. This issue resulted in a recall from European regulators to assess risk mitigation strategies for all marketed products employing sulfonic acid counter-ions to ensure that
sulfonate esters that could be potentially formed are controlled
to threshold of toxicological concern-based limits [31,33].
3.
Phase transitions during product development

Transformations between solid phases in dosage forms often
affects the drug release process and, therefore, it is important
to understand the mechanisms and kinetics of phase transformations and factors that may influence them [34]. The risk of
change to the physical form of the drug substance can be minimized by selecting a stable physical form of active pharmaceutical ingredient (API); however, it may also adversely
affect the bioavailability of the API. Thus, based on the collective information on the bioavailability of stable, metastable
and least-stable forms of API, an appropriate form should
be selected. After selection of a suitable form of the drug,
the process of formulation and conditions also decides the
solid state of the drug in the formulation. This phenomenon
is referred to as processing-induced phase transitions. In the
finished tablet dosage forms, in situ transformation also
affects tablet properties such as porosity, interparticulate
interactions and hardness. In situ phase transitions of
API in formulation has been exemplified with theophylline
(9) [35], thiamine hydrochloride (10) [36] and erythromycin
(11) [37], etc. Wet massing is one of the important steps in tableting, wherein Tantry et al. [38] observed complete phase
transition of stable anhydrous theophylline to theophylline
3.1
1243
monohydrate at elevated temperatures, which resulted in a

decrease in its dissolution rate. There was complete conversion of stable anhydrous theophylline (A) to theophylline
monohydrate (M) upon addition of water. During the drying
process, dehydration of the M form resulted in formation of
metastable anhydrous theophylline (A*), which was transformed to A. An increase in drying temperature accelerated
the A* to A transition; however, addition of PVP (a crystallization inhibitor) inhibited this transition. Interestingly, a
phase transition was noticed with the variation in method of
preparation of granules. The fluid-bed process produced granules that consisted almost completely of form A (stable form
of theophylline), whereas the high shear method yielded mixture of A and A* forms. This in situ transition led to decreased
dissolution rates of these tablets. Therefore, this phase transition between stable and metastable forms of API can have a
pronounced impact on product performance.
Chakravarty et al. [36] monitored phase transformation in
thiamine hydrochloride tablets on storage, which were formulated by direct compression and wet granulation methods. Thiamine hydrochloride was converted from non-stoichiometric
hydrate (NSH) to hemihydrate (HH) in stored tablets. There
were significant differences in the physicochemical properties
of tablets such as tablet microstructure, compact physical properties and product behavior. A marked increase in disintegration time, tablet volume and hardness upon wet granulation
of NSH with microcrystalline cellulose (MCC) was also
observed. However, when tablets of NSH-MCC were formulated by dry processing via direct compression, no change was
observed in properties except the in situ solid form converted
to needle-like HH crystals in all stored tablets. Longer storage
also led to crystal growth with reduced changes in properties.
Abbott Laboratories [37] reported dissolution failure of
erythromycin tablet formulation due to formation of in situ
isomorphic dehydrate. Specific lots of 12-month stability
samples of erythromycin dihydrate tablets (labeled claim
250 mg) failed in dissolution specifications. Lot 15, which
had a very good initial dissolution (> 99% at 60 min) failed
uniformly at the 12-month time point (71% released at
60 min). The tableting process for erythromycin involved
milling and drying, which was responsible for altering crystallinity and water content. During formulation development,
erythromycin dihydrate gets dehydrated, which gradually
binds with hydroxyl-rich excipients such as Mg(OH)2, and
thus results in delayed dissolution process.
Effect of polymorphism on bioavailability
To determine stability/instability of a drug, knowledge of
solid-state reactions and polymorphism [39] is important.
The selected solid form of a drug for development must
remain stable in formulation throughout the shelf life of the
API [40]. For formulation development, generally crystalline
form of drug with well defined and reproducible physical
properties is preferred [41]. The polymorphic form of a drug
shows variation in solubility, melting point, density, hardness,
3.2
1244
crystal shape, optical and elemental properties (e.g., vapor

pressure etc.) [42]. Moreover relative bioavailability of solid
compounds may vary markedly from one form to another.
The crystal structure affects stability and developability of
the crystallized product. The ritonavir (12, Novir) [43] story
illustrates the importance of transitions among crystal forms
(conformational polymorphism). In 1998, Abbott experienced a catastrophic example of physical instability of the
drug ritonavir [44,45]. Until 1998, Abbott had successfully manufactured hundreds of batches of the life-saving anti-HIV drug
ritonavir. These batches were formulated by dissolving ritonavir in polyethylene glycol/ethanol/polyoxyethylene/other components in a soft-gelatin capsule. In the spring of that year,
batches of the soft gelatin capsule started failing dissolution
specifications. Abbott quickly established that these failures
were caused by crystallization of a new, previously unknown,
less soluble polymorph of ritonavir. This new polymorph
(form 2) had about fourfold less solubility than the old form
and was supersaturated in formulation. Ultimately, Abbott
had to withdraw the soft-gel product from the market to
resolve the formulation issue. Abbott scientists then investigated the reason for the sudden appearance of form 2. The
prima facie reason for appearance of form 2 was formation of
a poorly purging cis-impurity that acted as the template for
the formation of cis-ritonavir that was less soluble. Investigation at a ritonavir-manufacturing site in Italy identified a
possible reason for the appearance of form 2 as a result of accidental seeding with this form [46]. Such transformations,
because they affect the solubility of the drug, can complicate
first-in-human trials and toxicological studies [45,47,48].
Another example of solid-state instability is chloramphenicol
palmitate (13), which when administered in suspension form
showed unsatisfactory clinical effect due to presence of biologically less active polymorphic form A [42]. It was discovered
that this compound exists in two different crystalline forms [49]:
the form A (b polymorphs -- biologically less active) [50] and
metastable form B (a polymorph -- active modification).
Upon oral ingestion of the suspension formulation of this
drug, blood levels of form A were found to be seven times
higher than form B [51]. The British and United States Pharmacopoeias specify a limit test which places an upper permitted
limit of 10% of less active b polymorph in a chloramphenicol
palmitate mixture (chloramphenicol palmitate oral suspension
USP) [52].
In April 2008, Schwarz Pharma recalled transdermal
patches of the dopamine agonist rotigotine (14) (Neupro
patch) in the United States and some in Europe because of
problems with the delivery mechanism and a quality defect.
Formation of crystals of rotigotine in Neupro (a matrix design
rotigotine transdermal system) led to the product recall and
subsequent discontinuation. The crystallization occurred
because of the appearance of a new unknown polymorph of
rotigotine within the patch. This new polymorph was found
to be thermodynamically more stable and less soluble than
that of the original form; therefore, it produced crystals in
patches which were visible to the naked eye as snowflakes.

These snowflake crystals consisted of pure rotigotine, the difference being that rotigotine molecules in this new polymorph
had a slightly different packing structure with each other compared with the original rotigotine form. As only soluble molecules of rotigotine can cross the skin, crystals must dissolve in
order to release drug molecules that can be absorbed. If this
does not occur, the amount of drug available to the patient
could be reduced. Therefore, the net effect of the snowflake
phenomenon is the possibility of reduced drug delivery and
therapeutic efficacy [53-55].
Although polymorphic behavior alters the solubility of
drugs, it does not necessarily alter the bioavailability as evidenced by phenylbutazone (15). In 1949, phenylbutazone
was used as a potent antirheumatic drug. As it is highly hydrophobic in nature (log P = ~ 4.15), it has very poor solubility in
acidic pH. It was observed that phenylbutazone has three
polymorphic forms namely form I, x and y. The maximum
drug concentration of form y was significantly higher over
the form x, because form y exhibited faster dissolution rate
(50% more) over the other forms. However, it was also
reported that there was no significant difference in bioavailability parameters of form I and x as the rate of absorption
of these crystals was identical [56-58].
The two forms of oxytetracycline, a dihydrate form and
HCl salt form have varying stability and water solubility.
The former was more stable compared to HCl salt form and
the aqueous solubility was opposite. Therefore, the relatively
insoluble hydrated base in the official preparation (British
Pharmacopoeia, 1973) may not be entirely satisfactory due
to its poor solubility. Thus, HCl salt was used for the preparation of formulations. However, Brice and Hammer in
1969 [59] reported that 16 lots of oxytetracycline hydrochloride (16) capsules (250 mg) from 13 suppliers showed drug
serum levels lower than that of the innovator product which
was thought to be associated with its instability. Further, in
1974 Barber et al. [60] observed the presence of different polymorph (form A) in the formulation, which had a slow dissolution rate compared with other polymorphs in 0.1 M HCl. For
example, tablets prepared using form A exhibited ~ 55% dissolution at 30 min, whereas the tablets prepared with form B
exhibited complete (~ 95%) dissolution at 30 min [61].
4.
Crystal engineering studies are important in the pharmaceutical industry to develop stable and robust solid dosage forms.
Solid-state properties have a great impact on physicochemical
and biopharmaceutical properties of drugs. The solid state is
important as it affects filtration, flow, tableting and dissolution. Although there may not be significant differences in bioavailability of drugs with different crystal habits, it is of
importance from a technological point of view. The injection
of a suspension-containing drug in crystal form is influenced
by its habit. Crystal habit also influences the ease of
compression of the tablet and the flow properties of the solid

form of the drug. For example, plate-like crystals of tolbutamide (17) created powder-bridging in the hopper of the tablet
machine and also led to capping problems during tableting [62].
Bristol-Myers Squibb recalled antihypertensive combination
of hydrochlorothiazide (18) and irbesartan (19) (Avapro tablets) in January 2011, due to problems associated with dissolution of irbesartan. This reduced solubility of irbesartan in
certain batches was the result of formation of a secondary crystal form of irbesartan. The formation of the less soluble crystal
form was due to tablet manufacturing changes. Detailed investigations revealed that an increase in granulation time resulted
in formation of these secondary crystals [63].
5.
Chirality
Determination of chirality is a part of typical development

track activity for preformulation monitoring. Generally, one
of the enantiomers does not have desired pharmacological
properties and thus unwanted enantiomer should be eliminated from the drug formulation. Once the separation technique is available, the inactive form should be excluded
considering economical point of view. Therefore, for development of NCE, the resolution method of an optically active
compound should be available at earlier stages of the discovery
process. As a regulatory requirement for IND submission, the
enantiopure form of the drug is essential. Thus, the selection
of right enantiomer for the market product must be decided
before patent application and IND submission. Racemic
mixture can only be considered if the unwanted enantiomer
racemizes rapidly (metabolically) to the desired enantiomer.
Heavy investment on wrong enantiomer can be avoided by
selecting a therapeutically active enantiomer [64]. For example,
sirolimus (20) (Rapamune) marketed by Pfizer (formerly by
Wyeth) is an immunosuppressive agent that was approved by
the Food and Drug Administration (FDA) in 1999. It is available as a clear, viscous oral solution containing 1 mg/ml sirolimus and coated tablets of 1 mg sirolimus as an active
ingredient. Inactive ingredients in the Rapamune oral solution are Phosal 50 PG and polysorbate 80 (nonaqueous
vehicles). Sirolimus is chiral (15 stereogenic centers) and is
produced as a single defined stereoisomer in solid state using
asymmetric synthesis. However, in aqueous solutions this was
interconverted into three isomers (A, B and C). Therefore,
selection and use of nonaqueous vehicles during product development eliminated major concerns with regard to solidstate properties of the drug substance, such as the potential
for polymorphic forms, particle size, surface area, intrinsic dissolution rate and oral bioavailability issues of sirolimus [65-67].
Bulk properties (particle size and size

distribution, flow, dissolution, etc.)
6.
Particle shape and size affect both primary and bulk powder
properties and play a decisive role in controlling dissolution [68].
1245
Knowledge of particle size and size distribution, flow properties and dissolution are key aspects that should be studied in
the field of dissolution science and during the formulation
development process [69]. The melting point of pharmaceutical
salts is often intrinsically related to their physicochemical properties. The APIs with low melting points often exhibit plastic
deformation during the formulation development process,
which can cause both caking and aggregation, and has an
impact on both flow and compressibility performance. These
in turn affect many critical quality attributes of the drug
product (with low dose) such as disintegration and in vitro
dissolution rates, friability and content uniformity [70].
Bastin et al. [19] demonstrated the importance of flow properties by studying physicochemical properties of various salts
of the anti-arthritic drug RPR 200765 (21). Among four
salt forms investigated (mesylate, camphorsulfonate, hydrochloride and hydrobromide), mesylate salt demonstrated
good handling properties such as good flow (required during
formulation stage) and a non-hygroscopic nature, allowing
straightforward capsule and tablet development. These flow
properties were superior to the alternative salts studied
(hydrochloride, hydrobromide and camphorsulfonate) [71].
7.
Hygroscopicity
Hygroscopicity of drug substances is an important parameter

to be considered in product development. The moisture
uptake rate varies for different drugs and excipients and is
dependent on environmental conditions and it often affects
stability of the drug in the dosage form [72]. NBI-75043 (22)
is a highly selective and potent H1 receptor antagonist that
was under evaluation for safety and efficacy in the treatment
of insomnia. Initially a tartrate salt of NBI-75043 was produced and dried to a constant weight, but it was found to
be ethanol solvate as determined by C, H and N in gas chromatography residual solvent analyses. In addition, the tartrate
salt was a hygroscopic solid with a low melting point
(~ 94 C). Moreover, ethanol solvate was found to readily
exchange ethanol for water within 1 week under accelerated
stability conditions (40 C/75% relative humidity). Due to
these inherent negative properties for API, this salt form of
NBI-75043 was recognized as being unacceptable for longterm studies. Neurocrine Biosciences found that the besylate
salt of NBI-75043 is crystalline in nature and exists in a single
polymorphic form with a higher melting point (165 -- 168 C)
and, thus, was found to be suitable for product development [73].
8.
Drug stability
Stability screening of drug candidates plays an important role

in drug discovery. It provides an overview of the stability of
the compound in a variety of pharmaceutical situations and,
thus, helps to identify potential liabilities that may affect the
drug development paradigm. The information obtained
from these studies can be used to: i) provide feedback to the
1246
chemistry team for modification of labile groups to improve

stability; ii) help development scientists to determine developability of the compound; iii) provide guidelines on compound
handling and storage; and iv) provide information to guide
stabilization strategies [3,48,74].
An orally administered levothyroxine sodium (23) product
did not remain potent and stable through their expiration
dates. Levothyroxine sodium was first introduced into the
market before 1962, without an approved new drug application (NDA), apparently in belief that it was not a new drug.
After that almost every manufacturer had regular recalls due
to reason of potency or stability issues. It has been reported
that levothyroxine sodium was unstable in the presence of
light, temperature, air and humidity [75,76]. As these products
were marketed without NDAs, manufacturers need not have
FDA approval each time after reformulating levothyroxine
sodium products. Manufacturers performed formulation
changes such as changed excipients, physical appearance of
coloring agents and other product aspects, which significantly
changed the potency of the drug (either decreasing or increasing by as much as 30%). In a few cases, these formulation
changes resulted in toxicity to people who were on the same
dosage for years. With the occurrence of potency issues, the
US FDA classified all orally administered drug products of
levothyroxine sodium as new drugs and made it mandatory
for all existing products to undergo the NDA process to
ensure consistent potency. As the drug is necessary to millions
of Americans, the FDA allowed marketing of these products
without an approved NDA until August 2000 and gave sufficient time to submit NDAs [77]. Teva Pharmaceuticals recalled
60 mL bottles of 0.05% fluocinonide (24) topical solution
USP in the United States because of degradation/impurities
which led to subpotency [78].
9.
Drug solubility
Solubility of a drug substance is a fundamental property that

should be evaluated early in the discovery phase. In reality, it
is difficult to predict the aqueous solubility due to the complicated solubilization procedure and solid-phase chemistry of
the drug candidate. A variety of approaches are employed at
different phases of drug discovery and development such as
in silico, kinetic and equilibrium solubility. Thermodynamic
or equilibrium solubility has been considered as the gold
standard for solubility determination [79], but kinetic solubility is more appropriate for early phase drug discovery [80].
A direct relationship exists between solubility of a molecule
and its dissolution rate. Drug penetration through lipid membranes depends on the lipophilicity of the molecule and, thus,
may be correlated with the partition coefficient value. Absorption of a drug depends on the correct balance between these
two opposite properties [81]. A lack of solubility affects the
ability of drug to achieve efficacious and toxicologically relevant exposures in animals. The solubility of compounds to
be tested is critical for all high-throughput screening (HTS)
test systems. As most of the in vitro test conditions also

require a pH of 7.4, there is a real chance that the concentrations apparently being tested are in fact not being attained. It
is difficult in HTS set up to ensure that the actual test concentrations have been achieved. Therefore, many times such tests
are typically run at relatively high concentrations to ensure
adequate safety margins (e.g., hERG channel liability) [82].
This characteristic also affects future developability and formulation efforts for compounds [83].
Beijnen et al. [84] reported the formulation of investigational cytotoxic drugs. Combretastatin A4 (NSC-81373, 25)
is a natural product, isolated from dry stem wood of the South
African tree Combretum caffrum, with excellent in vitro anticancer activity, but no significant in vivo activity. Formulation
of combretastatin A4 was problematical due to limited aqueous solubility and chemical instability of the drug in solution,
which was aggravated by light. The most promising formulation was one using the PET solvent system. PET is a mixture
of polyethylene glycol 400 (60%), polysorbate 80 (10%) and
ethanol (to 100%). In a preliminary murine toxicological
study, severe irritation at the injection site was noticed.
Attempts were also made to use other formulation approaches
such as using emulsions; however, the physicochemical properties of combretastatin A4 did not allow these attempts to
succeed. Subsequently prodrug approach showed promise
wherein the phosphate ester proved to have adequate solubility and stability in aqueous solution; however, this candidate
was found to be inactive in vivo and current research is
directed toward identifying other suitable prodrugs.
Flavopiridol [5,7-dihydroxy-8-(4-N-methyl-2-hydroxypyridyl)-6-chloroflavone hydrochloride, 26] is a flavonoid with
weak electrolyte properties and poor aqueous solubility
(0.02 mg/mL). Flavopiridol is currently under consideration
as a parenteral treatment for breast tumors [85]. A number of
methods have been tried to improve solubility of flavopiridol
such as cosolvency, complexation and pH control. Because of
its low intrinsic solubility, precipitation of the solubilized
drug, when diluted with blood upon injection, was a problem.
Li et al. [86] studied precipitation of the drug in parenteral formulation containing up to 10 mg/mL of flavopiridol using a
static serial dilution technique. There was no precipitation
in formulations containing 2 and 5 mg/mL of flavopiridol
in 30% 2-hydroxypropyl-b-cyclodextrin (HP-b-CD) -0.1 M
citric acid at pH 5.8 and 10 mg/mL of flavopiridol in 30%
HP-b-CD--0.1 M citric acid at pH 3 [86,87]. This improvement in solubility of flavopiridol was thought to be due to
better solubility of the HP-b-CD complex of flavopiridol at
the abovementioned pH.
10.
Assessment of possible incompatibilities between drug and

excipients is a key element of preformulation. Formulation
of a drug substance involves being blended with different excipients to improve its manufacturability and to maximize the
products ability to effectively administer the drug dose.

Most excipients have no direct pharmacological action but
they impart useful properties to the formulation. Apart from
this, they can also give rise to inadvertent and/or unintended
effects such as increased drug degradation. Physical and chemical interactions between drugs and excipients may affect
chemical nature, stability and bioavailability of drug products,
and subsequently their therapeutic efficacy and safety [88].
Incorporation of additive(s) to an intravenous fluid may
alter inherent characteristics of the drug substance present,
resulting in parenteral incompatibility. Physical compatibility
of various components in parenteral nutrition (PN) solutions
has been a concern, particularly solubility of minerals such as
calcium and phosphate [89]. A safety alert was issued by the
FDA in 1994 regarding hazards of precipitation associated
with PN. Admixtures were thought to contain precipitates
of calcium phosphate and patient autopsies revealed diffuse
microvascular pulmonary emboli containing calcium phosphate [90,91]. During January 1994, two patients at a federal
hospital died suddenly while receiving a three-in-one (i.e.,
amino acid, carbohydrate and lipid) peripheral PN admixture.
Clinical diagnosis in both patients was pulmonary embolism.
The autopsies revealed amorphous deposits of calcium phosphate in pulmonary microvasculature of both patients [92].
The size of the particles was not evaluated, but the reason
behind the deaths was considered to be due to a faulty mixing
sequence, deficient inline filtration and a short time from
compounding to administration [93,94].
An example of therapeutic incompatibility is Coumadin
tablets. Bristol-Myers Squibb recalled Coumadin (warfarin
sodium, 27) crystalline 5 mg tablets (lot number 9H49374A)
because of efficacy issues. In these formulations, isopropanol
was used to keep the active ingredient in a crystalline state.
However, poor quality isopropanol had a risk of Coumadin
being less potent or overly potent and certain lots were recalled
because of isopropanol not meeting quality specifications.
Recalls in these batches were decided because if a drug becomes
less potent, there is an increased risk of blood clots, heart attack
or stroke, and if it becomes too potent there is more risk of
bleeding [95].
Metformin (28) (Starlix), a product of Novartis, which is
intended for treating type II diabetes, is an example of charge
interaction reported by Hollenbeck et al. [96]. Novartis
observed low percentage recovery during the analytical
method development and validation of the combination
bilayer product Starlix. The purpose of bilayer was to separate
the drug (metformin) from croscarmellose sodium. When
these two are present in solid state, the charge interaction is
not expected due to low moisture content in the tablet
(< 2%). However, in solution form, the positively charged
metformin and negatively charged croscarmellose sodium
underwent a charge interaction, which led to a 4 -- 8% loss
in metformin recovery in the tablets. In solution form, this
recovery was very low (between 55 -- 73%) confirming the
interaction. This issue was resolved by incorporating arginine
1247
into the formulations, which is a competitor for binding sites

on croscarmellose sodium. Arginine has stronger interaction
with croscarmellose sodium than metformin, thus, enabling
a complete recovery of metformin in tablet formulation [97].
For a detailed account on interactions and incompatibilities
of APIs with pharmaceutical excipients, a specific review [88]
on this topic should be referred to.
Biopharmaceutical aspects -- absorption,

distribution, metabolism and excretion
11.
A total of 90% of compounds reaching an IND filing fail to

be a NDA [98]. The key factor pursued in many lead discovery
and optimization programs is high in vitro potency/activity
(as low as in the nanomolar range). At preclinical stage, an
optimization of physicochemical and biopharmaceutical
properties such as solubility, selectivity, cellular activity and
ADMET properties may reduce the failure rate in clinical
trials [99-106]. Compounds that are identified as poorly soluble
and/or which show poor bioavailability as well as crossspecies metabolism necessitates additional formulation efforts
at the developmental stage [106-111]. The most cited example is
lopinavir (29), which is a potent antiretroviral drug. However,
it has high plasma protein binding and poor bioavailability.
Formulation in combination with ritonavir (a fixed dose combination, Kaletra), a CYP3A inhibitor, was then developed
to overcome bioavailability issues [112,113].
Another antiretroviral drug, saquinavir (30) belongs to the
class of protease inhibitors. Two formulations have been
marketed; a hard-gel capsule formulation of mesylate salt
(Invirase) was approved in 1995, wherein ritonavir in combination with saquinavir was administered in order to increase
saquinavir bioavailability. This hard gelatin capsule formulation was poorly absorbed and led to viral resistance in many
patients. For this reason, in order to improve bioavailability,
another formulation (Fortovase) was approved in 1997 -- an
orally administered microemulsion in the form of a softgel capsule formulation of saquinavir. In May 2005, Roche
announced market withdrawal of Fortovase owing to reduction
in demand, possibly because Invirase boosted with ritonavir
was more effective compared with Fortovase [114]. Bioavailability of other protease inhibitors such as atazanavir (31) [115]
(Reyataz marketed by Bristol-Myers Squibb was approved
in 2003); darunavir (32) [116] (Prezista formerly known as
TMC114 was approved in 2006) and etravirine (33) [117]
(Intelence was approved in 2008, marketed by Tibotec, a subsidiary of Johnson & Johnson) were found to be increased
when given in combination with lopinavir/ritonavir. Chemical
structures of drugs 29 -- 33 are shown in Figure 3.
12.
commercialization involves several steps that traditionally

occur in a series [118]. The average cost of taking a candidate
from the discovery stage to commercialization is estimated
to exceed US$800 million, with an average development
time span of ~ 15 years, and a success rate of only 1 in
5,000 discovery candidates reaching the market [119]. HTS
and combinatorial chemistry technologies have been developed in the past two decades to speed up initial drug discovery
stages such as synthesis of a large number of diversely oriented
compounds and the ability to screen them quickly in a shorter
time. In contrast, these technologies have produced large
number of hits with poor physicochemical and ADMET
properties which are responsible for high attrition rate at further stages of drug discovery. Several complementary in silico
and in vitro strategies have also emerged to screen these compounds and assess their potential to become lead candidates.
Some of the advantages of HTS may be combined with
analyses of structure--activity relationships to direct rapid,
sometimes automated, iterative chemistry. Prediction of
potency at target, potency at likely toxicity sites, potency in
cellular assays and prediction of ADMET at early stages of
drug discovery research is now gaining importance [120,121].
Compounds emerging as hits from these screening processes
are characterized further and tested in vivo for safety and
efficacy [107]. A number of drugs have been removed from
the market due to safety/efficacy concerns and economic
factors [122]. Elements that are essential to take a new lead
candidate through the preclinical development process are
numerous. These include synthesizing sufficient compound
for safety assessment, formulating and characterizing drug
product, determining the drugs bioavailability and metabolic
profile, and conducting safety studies to determine the drugs
toxicity. Better understanding of the chemical and pharmaceutical properties of newly synthesized molecules, leading
to better pharmacokinetic parameters, certainly reduces the
failure rate of preclinical and early clinical molecules [123,124].
After pharmacological and toxicological screening, the best
compound(s) from the biopharmaceutical point of view could
be selected based on physicochemical parameters such as solubility, dissolution rate, lipophilicity, hygroscopicity, pKa,
polymorphism, stability and particle characteristics at earlier
stages with the highest possible accuracy. These properties
continue to be referenced throughout API scale-up process
chemistry and good manufacturing practices [125,126]. Therefore, at an early stage, physicochemical studies have a significant part to play in anticipating formulation problems and
in identifying a logical path in dosage form technology.
Such studies may also result in reduction of development
costs [127,128]. Successful implementation of this process results
in generation of sufficient data to file an IND application [129].
Preformulation and IND approval

Preformulation requisites
Drug research is a very complicated endeavor which includes
several diverse disciplines united with a common goal of
developing novel therapeutic agents. Due to growing
12.1
Drug research and development is a unique multidisciplinary

process to identify novel therapeutic agents. The process of
taking NCE from concept to clinic and eventually to
1248
NH2
O HO
HN
HN
N
N
NH HN
H3CO
O
O
OHO
NH
HN
OH
N
NH
NH
NH
29 Lopinavir
30 Saquinavir
31 Atazanavir
H2N
NH2
HN
N
O
OCH3
O
Br
O
H
HN
O
N
NH
OH
32 Darunavir
33 Etravirine
Figure 3. Chemical structures of drugs 29 -- 33 discussed in ADME-related case studies.
complexity of drug substances, development of a quality drug

product and a reproducible manufacturing process becomes
more challenging and costly. The method should yield consistent high-quality drug products that should not be affected by
variation within the drug substance, excipients and raw materials. In the early stage of product development, a fundamental understanding of the physicochemical properties of the
drug substance potentially influences performance and manufacturability of the drug product. The study of physicochemical properties of a drug substance is usually conducted during
preformulation research. In general, preformulation work can
start as early as during biological screening, in which diverse
compounds are screened for desired activity. However, an
extensive physicochemical characterization of a drug substance will not usually start until one or more potential candidates are identified and taken into clinical testing during the
investigational stages. The information and knowledge gained
from preformulation studies also help in accelerating development of new therapeutic entities. For example, selection of
compounds that have physical properties favorable for oral
absorption and certain types of process operations can facilitate rapid progress of these compounds at later stages of
drug product development. Generally, preformulation studies
start with an exploration of solubility, permeability, stability,
hygroscopicity, particle size, polymorphism and so on. Some
of these characteristics are interrelated and their analysis may
need to be considered in combination or simultaneously [130].
Drugs penetrate across the epithelium via transcellular or
paracellular pathways. Lipophilic drugs prefer the transcellular
route and hydrophilic drugs penetrate primarily through the
paracellular pathway, which involves passive or altered diffusion through intercellular spaces [131]. In active transport,
membrane proteins act as carrier molecules to transport drugs
across cell membranes [132]. Factors that affect poor solubility
and thereby poor bioavailability are high crystallinity/

high melting point and hydrophobicity or high log P value.
The n-octanol/water partition coefficient is the ratio of concentration of compound in n-octanol to that in water under
equilibrium. Log P is a parameter that determines lipophilicity of a molecule and has wide application in prediction of
biological activities and ADMET [133]. In general, if log
P = 0, there is equal distribution of the drug in both phases.
Log P > 0 is indicative that the drug is lipid soluble and
log P < 0 means the drug is water soluble. Therefore, the
higher the log P value, the higher the affinity for lipid membranes. Values of log P that are too high (> 5) or too low
(< 3) may be associated with poor transport characteristics [134,135]. Physicochemical and pharmacokinetic properties
of a drug will decide rationality of product development or
suitable drug delivery systems.
For topical and transdermal delivery, physiochemical
factors such as solubility, crystallinity, molecular weight
(< 600 Da), melting point (< 200 C) and Log P (between
-1 and 4) must be considered. The higher value of Log P
points to a potentially higher ease of penetration of the compound into cells of living organisms [136-138]. There is not an
absolute standard for solubility or dissolution for drugs given
orally. The acceptable level of solubility will differ from compound to compound based on dose and permeability. If the
dose is low and permeability is good, then even poorly soluble
compounds will be well absorbed. However, high-dose drugs
that are poorly soluble are much more likely to have limited
solubility. These compounds are better candidates for solubility enhancement and prodrug strategies. Typically, partition
coefficients in the range of 100 -- 1,000 (log P = 2 to 3) are
required for efficient passive transcellular transport. Extremely
lipophilic compounds (log P > 3.5) are associated with
decreased absorption [139]. Compounds that have a low
1249
aqueous solubility (< 1 mg/mL) may already possess inherent

sustained-release potential as a result of their low solubility [140]. For ophthalmic drug delivery, favorable parameters
of drug are: log P value of 2 to 3 and molecular weight
is < 500 Da [141]. In the case of a nasal delivery system, nasal
absorption drops-off sharply for lipophilic drugs with a
molecular weight > 1,000 Da [142]. Drugs in a nonionized
state are absorbed due to a high apparent partition coefficient
(more lipophilic). Commonly intranasal drugs are administered as molecularly dispersed forms such as solutions. The
allowable volume of solution for intranasal administration
is relatively low and, therefore, drugs with low aqueous
solubility and/or requiring high doses may present a problem.
The profile of an ideal drug candidate for nasal delivery
is molecular weight < 500 Da, log P < 5 and aqueous
solubility < 50 mg/mL [143]. Drug solubility and dissolution
rate are important, especially if it is administered as a solid
dosage form (e.g., a powder). Powder morphology and particle size influences amount and pattern of drug deposition
inside the nasal cavity [144-146]. Based on physicochemical
drug properties, a suitable drug delivery approach can be
selected and/or drug properties can be modified in terms of
solubility, log P value, crystallinity, hygroscopicity and so on
to achieve required criteria for a targeted delivery system.
Regulatory requirements
A preformulation report of a new molecule constitutes determination of chemical, manufacturing and control (CMC)
properties, analytical profiling, thermodynamic and physicochemical properties, pharmaceutical and mechanical properties, solid-state characteristics, biopharmaceutical properties,
excipient compatibility studies and stability. These drug
substance properties should be emphasized in the CMC/
pharmaceutical development section of IND. This provides
early insights to both industry and regulators regarding the
potential significance of physicochemical properties on drug
product quality and manufacturing processes [147]. It is now
accepted that properties of a given drug substance are to be
thoroughly investigated early during the phases of development and results of these findings must be included in the
CMC section of IND. The CMC section consists of information pertaining to chemical composition, manufacturing
methods, stability and controls used for manufacturing the
drug substance and drug product. One should know chemical
stability as well as activity of the product. This information is
assessed to ensure that the company can adequately produce
and supply consistent and active batches of the drug. Efforts
are currently under way within the International Conference
on Harmonisation to develop a common technical document
that will harmonize CMC regulatory requirements for global
development and marketing. Preparation of CMC sections
according to European Union and United States guidelines
results in two formally different NDAs. Components of CMC
sections of the EU Marketing Authorisation Applications and
US NDA are very much the same [64,148,149].
12.2
1250
13.
Conclusion
In summary, the article has provided critical account on the

significance of preformulation studies in the drug development process. To facilitate clinical development and to reduce
attrition rate, a thorough study of physicochemical properties
of drug candidates is desired. This also serves as the foundation
for developing robust formulations.
14.
Expert opinion
Collaboration of medicinal chemists and formulation scientists in drug discovery research is essential to identify a drug
candidate that has the best chance of clinical and eventually
commercial success. The partnership between medicinal
chemists and formulation scientists in drug discovery produces NCE with structural modifications in order to improve
solubility, stability, permeability and oral bioavailability.
The role of formulation scientists has been recognized for preparing formulations for preclinical in vivo studies and for
identification of final solid-state forms of drugs. Apart from
this, the team work between pharmaceutics and medicinal
chemistry departments at earlier stages of drug discovery
increases the speed of preclinical evaluation and reduces attrition during the development process. The performance of
solid dosage forms is reliant on the physicochemical properties of the active ingredient and excipients. Before going for
Phase I clinical studies, excipients used for the formulation
development process should be identified. The purpose is to
ultimately prevent unnecessary and very costly changes
including time and overall development cost in subsequent
steps. The goal is to identify critical parameters important in
the development of a stable, effective and safe drug delivery system or dosage form. Table 1 depicts examples of drug products
wherein preformulation data showed impact on the drugs
development or its recall from the market. Examples of product recall are primarily because of inadequate preformulation
data where different/more preformulation data might have
avoided market loss.
Most companies perform salt screening in order to have
a molecule with appropriate physicochemical properties
such as crystallinity, low hygroscopicity, dissolution rate, solubility, bioavailability and stability. Improper salt form selection may lead to instability in the final product as seen for
REV-5901 (3) where hydrochloride/sulfate salt was found to
be unstable. The most commonly used pH modifiers for
acidic drugs are sodium, calcium, potassium and so on. For
basic drugs, they are hydrochloride, mesylate, sulfate, citrate
and hydrobromide. REV-5901 is a base with a pKa value of
3.7 and the pH solubility profile of REV-5901 showed that
the pHmax of the compound was 1 indicating that the salt
form would exist only at pH < 1. Therefore, only two salt
forms (hydrochloride and sulfate salts) could be prepared.
A salt with weaker acids such as phosphoric, acetic, lactic
and tartaric acid was not feasible. Another interesting point
Biopharmaceutical aspects-ADME
Drug solubility
Chirality
Bulk properties (particle
size and size distribution,
flow, dissolution, etc.)
Hygroscopicity
Drug stability
Salt selection and stability
Preformulation parameter
Drug product
Lopinavir (29)
Saquinavir (30)
Metformin (28)
Warfarin sodium (27)
Flavopiridol (26)
PN
NBI 75043 (22)

Levothyroxine sodium (23)
Fluocinonide (24)
Combretastatin A4 (25)
Chloramphenicol palmitate (13)

Rotigotine (14)
Oxytetracycline hydrochloride (16)
Tolbutamide (17)
Hydrochlorothiazide (18) and irbesartan (19)
Rapamune (20)
RPR 200765 (21)
Erythromycin (11)
Ritonavir (12)
Thiamine hydrochloride (10)
Theophylline (9)
Nelfinavir mesylate (8)
Chlortetracycline (1)
Penicillin G (2)
REV-5901 (3)
LY333531 (4)
Diclofenac (5)
Dibenzo (b,f)oxepen-10-ylmethyl-methyl-prop-2-ynyl-amine
hydrogen maleate (6)
L-649923 (7)
Table 1. Preformulation case studies.
Besylate salt was more pharmaceutically acceptable than tartrate salt

Unstable in the presence of light, temperature, air and humidity
Degradation/impurities leading to sub-potency
Limited aqueous solubility and chemical instability -- phosphate
ester was inactive
Precipitation in the parenteral formulation due to poor solubility
Admixture contained precipitate of calcium phosphate, which caused
diffuse microvascular pulmonary emboli.
Reduced potency of warfarin sodium due to use of
poor quality isopropanol
Very low recovery due to interaction between positively charged drug and
negatively charged excipient (croscarmellose sodium)
To overcome bioavailability issue given with ritonavir (a CYP3A inhibitor)
Increase in bioavailability when combined with ritonavir
[28]
Free base was very unstable, but the calcium salt was more
pharmaceutically promising than the sodium, ethylenediamine
and benzathine salts
Withdrawn from market due to elevated levels of ethyl methanesulfonate
(cancer-causing contaminant)
Phase transition of stable anhydrous theophylline to
theophylline monohydrate due to wet granulation, which resulted
in decrease in dissolution rate
Conversion of stable thiamine hydrochloride to NSH
due to wet granulation
Conversion to erythromycin dihydrate due to milling and drying
Reduced solubility in the marketed formulation due
to existence of new polymorph
Discovery of presence of biologically less active crystal form
Presence of less stable new polymorphic crystals
Discovery of less soluble new polymorph
Plate-like crystals cause tableting problems
Existence of less soluble crystal of irbesartan due to longer granulation time
Converts to three isomers in aqueous solution with reduced bioavailability
Mesylate salt demonstrated good handling properties among the
four salts (camphorsulfonate, hydrochloride and hydrobromide)
[113]
[114]
[96]
[95]
[86]
[90]
[73]
[77]
[78]
[84]
[42]
[54]
[60]
[62]
[63]
[67]
[71]
[37]
[151]
[36]
[38]
[31]
[21]
[20]
[22]
[23]
[24]
[26]
Refs.
Calcium salt was very stable compared to hydrochloride salt

Potassium salt was less hygroscopic, but had unpleasant metallic taste
Hydrochloride salt unstable
Low aqueous solubility of free base of API; mesylate salt form was optimal
Solubility of sodium salt better than other prepared salt forms
Maleate salt was more stable than the free base
Preformulation observations
1251
was if the microenvironmental pH rises above 1, the hydrochloride/sulfate salt gets converted to free base. Therefore,
REV-5091 was preferred as a free base over the salt forms.
Trace impurities found during salt formation plays a significant role in the stability of formulations and may affect
potency of API. The starting material used for salt form preparation may also give rise to formation of impurities as a
by-product as seen in the case of nelfinavir mesylate (8).
Another parameter to be studied during the preformulation
stage is polymorphism and phase transitions. These should be
investigated during initial stages of development. In situ phase
transitions during product development (manufacturing
processes and processing conditions) may affect/alter solubility of drug and thus the bioavailability. The manufacturing
processes such as wet granulation [as in case with theophylline
(9), thiamine HCl (10)], milling and drying [as observed with
erythromycin (11)] may have pronounced effect on dissolution rate and stability of drugs. Results of these studies must
be incorporated in the CMC section of NDA. This information is required to demonstrate control over manufacturing
processes. Existence of different crystal forms should be studied because it may impart either harmful or helpful characteristics to particular formulations in terms of bioavailability.
The most cited example is ritonavir (12) and oxytetracycline
HCl (16) wherein new polymorphic forms have less solubility
and thus reduced bioavailability. Discovery of a new crystal
form of chloramphenicol palmitate (13) was biologically less
active thus making formulation less effective. In the case of
rotigotine (14), the new polymorph discovered was less stable.
For this reason, polymorphic study is crucial during the preformulation stage and will decide commercial success of the
final product. The crystal structure of a compound will decide
its physicochemical properties such as crystal habit, melting
point, solubility, rate of desolvation, color, mechanical properties and chemical stability. Plate-like crystals of tolbutamide
(17) were not suitable for tableting and, therefore, not manufacturable. Thus, understanding of these properties during
product development will be beneficial.
In the pharmaceutical scenario, particle size and size distribution affects the intrinsic dissolution rate, which is one of the
decisive parameters of drugs after administration. Shape characterization is vital here as different crystal faces dissolve at different rates. At the preformulation stage, one should identify
particle shape and size distribution in order to produce formulations with desired efficacy and with economical production techniques. Good flow properties are preconditions for successful
manufacturing of dosage forms (tablets and hard gelatin capsules). Appropriate fluidity of materials is required for transportation of powder fill/granules through the hopper of the tableting
machine. Elongated particle shape and small particle size may
cause high tablet weight variations, strength, unacceptable blend
uniformity and difficulty in filling containers and dies. Powder
flow is affected by numerous parameters including purity, crystallinity, electrostatic forces, mechanical properties (brittleness,
elasticity), density, size, shape, surface area, moisture content,
1252
direction and rate of shear, storage container dimension and particle--wall interaction. In the case of RPR 200765 (21), mesylate
salt was found to have better handling properties over sulfonate,
hydrochloride and hydrobromide salts.
Drug stability is an essential component of preformulation
testing and preformulation scientists collaboratively work
with analytical departments to develop stability-indicating
assays. During early stages, a perfect stability-indicating assay
may not be available because initial drug lots may not be pure
and purity is improved as the molecule progresses to subsequent development stages. Therefore, the intention of preformulation scientists is to broadly define conditions under
which the drug would be stable. In the case of levothyroxine
sodium (23) it was not stable throughout its shelf life and after
marketing it was found that the reason behind less potency
was a stability issue with levothyroxine sodium. It was sensitive to light, temperature, air and humidity, thus, loss of
potency was the reason behind product recall.
Determination of solubility during preformulation testing
is a decisive parameter during formulation development. Drug
solubility is one of the physicochemical parameters that receive
a lot of attention during preformulation testing. The BCS paradigm can be used to develop strategies for enhancing drug solubility and/or permeability. Generally, the absorption rate constant of
drugs varies by over only ~ 50-fold range (0.001 -- 0.5 mg/min)
whereas drug solubility can vary over six orders of magnitude
(0.1 g/mL -- 100 mg/mL) [150]. Hence, the formulator has superior flexibility in altering the drugs solubility over its permeability. Optimization of drug solubility may be more fruitful if
permeability is overcome by increasing drug solubility, to provide
high drug concentration at the absorption site. However, this may
be difficult if the dose is very high. Alternative formulation
approaches could be considered if the drug is poorly soluble. In
the case of flavopiridol (26), researchers formulated flavopiridol
with HP-b-CD and citric acid to keep the drug in a solubilized
form so that it would not precipitate upon injection.
The role of the preformulation team at every stage of the
drug discovery and development process is to select appropriate
methods to guide or alert other development teams about drug
solubility and permeability issues. There have been consequences
observed of formation of new impurities, incomplete mass balance, destruction of dosage form, unnecessary multiplicity of prototype formulations and changes in physicochemical properties
(stability, solubility, dissolution profile, degree of crystallinity
and hygroscopicity) due to inadequate data on the drug--excipient
interaction. The reason behind this might be incomplete/
insufficient drug--excipient interaction studies at the preformulation stage, which can be one reason for inability to obtain successful drug registration. The bilayer tablet of metformin (28) was
recalled due to a very low recovery of API. This has been attributed to the use of a negatively charged excipient (i.e., croscarmellose sodium), which had an interaction with metformin.
Throughout the process of drug discovery, a carefully
planned preformulation study provides crucial data and
information regarding drug substance and knowledge of
manufacturing technology before going for formulation

development activities. Negligence toward assessment of any
of the preformulation parameters may lead to a significant
impact on the total development activities.
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Affiliation
Sonali S Bharate1 & Ram A Vishwakarma2
Author for correspondence

1
Indian Institute of Integrative Medicine (CSIR),
Canal Road, Jammu-180001, India
2
Director,
Indian Institute of Integrative Medicine (CSIR),
Canal Road, Jammu-180001, India
E-mail: ram@iiim.ac.in
1257

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Impact of preformulation on drug development

Available from: Sonali S Bharate

Sonali S Bharate & Ram A Vishwakarma

Indian Institute of Integrative Medicine (CSIR), Jammu, India

Salt form selection and its

Polymorphic phase transitions

Crystal habit and druggability

Bulk properties (particle size

Introduction: Preformulation assists scientists in screening lead candidates

and size distribution, flow,

Preformulation and IND

Keywords: drug development, investigational new drug, preformulation, product recall

Preformulation studies (physicochemical and biopharmaceutical properties) play a

S. S. Bharate & R. A. Vishwakarma

Preformulation research helps in selection of NCEs for

This box summarizes key points contained in the article.

Salt form selection and its stability

Expert Opin. Drug Deliv. (2013) 10(9)

Impact of preformulation on drug development

A) Molecular structure B) Chemical analysis

penicillin G (2) was much less hygroscopic than sodium salt;

Expert Opin. Drug Deliv. (2013) 10(9)

S. S. Bharate & R. A. Vishwakarma

Figure 2. Chemical structures of drugs 1 -- 28 discussed in preformulation-related case studies.

Expert Opin. Drug Deliv. (2013) 10(9)

Impact of preformulation on drug development

propensity to undergo intramolecular esterification to form

Polymorphic phase transitions

Phase transitions during product development

Expert Opin. Drug Deliv. (2013) 10(9)

S. S. Bharate & R. A. Vishwakarma

monohydrate at elevated temperatures, which resulted in a

crystal shape, optical and elemental properties (e.g., vapor

Expert Opin. Drug Deliv. (2013) 10(9)

Impact of preformulation on drug development

patches which were visible to the naked eye as snowflakes.

Crystal habit and druggability

compression of the tablet and the flow properties of the solid

Determination of chirality is a part of typical development

Bulk properties (particle size and size

Expert Opin. Drug Deliv. (2013) 10(9)

S. S. Bharate & R. A. Vishwakarma

Hygroscopicity of drug substances is an important parameter

Stability screening of drug candidates plays an important role

chemistry team for modification of labile groups to improve

Solubility of a drug substance is a fundamental property that

Expert Opin. Drug Deliv. (2013) 10(9)

Impact of preformulation on drug development

test systems. As most of the in vitro test conditions also

Assessment of possible incompatibilities between drug and

products ability to effectively administer the drug dose.

Expert Opin. Drug Deliv. (2013) 10(9)

S. S. Bharate & R. A. Vishwakarma

into the formulations, which is a competitor for binding sites

Biopharmaceutical aspects -- absorption,

A total of 90% of compounds reaching an IND filing fail to

commercialization involves several steps that traditionally

Preformulation and IND approval

Drug research and development is a unique multidisciplinary

Expert Opin. Drug Deliv. (2013) 10(9)

Impact of preformulation on drug development

Figure 3. Chemical structures of drugs 29 -- 33 discussed in ADME-related case studies.