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When a promising new chemical entity is synthesized, it needs transformation to appropriate
formulation in order to show a better and desirable action at appropriate site. Preformulation
study is a phase which is initiated once the new molecule is seeded. In a broader way, it deals
with studies of physical, chemical, analytical, and pharmaceutical properties related to
molecule and provides idea about suitable modification in molecule to show a better
performance. Study of these parameters and suitable molecular modification can be linked to
generation of effective, safer, stable, and reliable pharmaceutical formulation. Therefore,
preformulation study is an approach for generation of pharmaceutical formulation which
utilizes knowledge and area application of toxicology, biochemistry, medicinal chemistry, and
analytical chemistry.

At various stages during development, it is essential to understand the physicochemical
characteristics of compounds or biological entities that can affect their development into final
products. Data acquired from such preformulation studies forms an important basis for
understanding the potential pharmacokinetics of a drug in humans and animals and the
opportunities and limitations for process change as the product is scaled up in manufacture.
Preformulation studies are also performed to predict the stability of the formulation during
manufacture, transport and storage and thus determine the shelf life of the marketed product.

Discovering and developing new medicines is a long, complex and expensive process and the
failure rate is high during the process. To minimize attrition it is essential, therefore, to
understand the physicochemical characteristics of compounds or biological entities that are
candidates for development into final products.

At various stages during the development of a new medical product the candidate drug must be
formulated into a dosage form that is appropriate for the intended study e.g. in vitro screening
using chemical, physicochemical or biological assays, pre-clinical in vitro laboratory safety tests,
in vivo efficacy and safety studies in relevant animal species, first-in-human studies to
determine the optimum drug to progress into clinical development, initial volunteer/patient
studies and full-scale clinical trials






The nature and composition of the formulations will be different for each stage of development
but the formulation chosen for full-scale clinical trials must, as far as possible, be the same as
the product that is intended for marketing. Otherwise extensive clinical comparative trials may
be required to demonstrate the similarity between the formulation used in the clinical trials
and that proposed for subsequent marketing.

To ensure that the various formulations are optimized for their intended use, pre-formulation
studies should be conducted not only to evaluate the characteristics of candidate drugs but also
potential formulation excipients, and their interactions with drug substances, in order to select
appropriate formulation ingredients. In addition, preformulation studies should assess the
effect of possible conditions of preparation, manufacture and storage on stability, so as to give
confidence that a reliable assessment of the candidate drug has been performed during
development and in regular, post-marketing, use.

Data acquired from preformulation studies also forms an important basis for understanding the
potential pharmacokinetics of a drug in humans and animals.

In addition, as the chosen product is scaled up in manufacture and/or further process
development is carried out e.g. to use alternative equipment or technologies; preformulation
data can be a useful source of information to understand the opportunities for and limitations
to process change.

Furthermore, a number of the characteristics measured in preformulation studies can be used
to predict the stability of the formulation during manufacture, transport and storage so as to
determine the shelf life of the marketed product.

Preformulation studies can therefore be defined as; Laboratory studies to determine the
characteristics of active substance and excipients that may influence formulation and process
design and performance. It has been described as “Learning before doing”.




Goals Of Pre-formulations:

• To formulate an elegant, safe, efficacious dosage form with good bioavailability. • To
formulate new dosage form of already existing drug. • Determination of all the properties of
drug and the best suitable dosage form for the drug molecule.

Protocol of pre-formulations:

• Pre-formulation protocol is a plan or blueprint as how the pre- formulation
experiments/procedures are designed. A written plan from starting of the procedures
to be conducted till the decision points on what constitutes acceptable results.

Discovery of a new drug entity is a huge milestone in science and it becomes even more
important if it passes toxicity screening as the potential benefits overweigh the side effects. The
ultimate effect of the new chemical entity depends on its availability at the site of action once it
is administered through appropriate route in appropriate form. So for this reason, a new
challenge is offered after successful pharmaceutical and toxicological screening that is to
transform potential active new drug entity into a pharmaceutical formulation. It can be broadly
elaborated as “a phase which works on study of physical, chemical, analytical, pharmacokinetic,
and pharmacodynamics properties of new chemical entity and utilize the obtained results to
design and develop an effective, stable, and a safer dosage form.” Preformulation study is there
for the multidisciplinary approach and utilizes involvement of several aspects of pharmacology,
toxicology, clinical pharmacy, biochemistry, medicinal chemistry, and analytical chemistry
(Below figure). The preliminary objective of preformulation phase or study is to lay down
foundation for transforming a new drug entity into a pharmaceutical formulation in such a way
that it can be administered in a right way, in right amount, and on perhaps the most important
at right target. The secondary objective preformulation study is to provide longer stability to
the formulation by proper designing and protecting drug component from environmental
condition and to evaluate performance of developed formulation.














Optimization of an active molecular entity:

Following the successful pharmacological screening of an active molecular entity, one has to be
sure about the appropriate molecular form of active molecular entity. The optimization of
molecule is needed with respect to stability of molecule under normal environmental condition
or with respect to enhancing the performance of that molecule like bioavailability and stability.
To inbuilt these virtues into a molecule, efforts are made to optimize a molecule inform of salts,
solvates, polymorphs, and more importantly prodrug.

1. Salts:

Nearly half of the drug molecules that are marketed as drug products are administered in salt
form. Converting a molecule into a salt form is perhaps the most widely used approach to
significantly enhance the performance of a molecule. This improvement can be made in area
such as follows:

Performance (increased solubility and bioavailability)

Improved stability (hydrolytic and thermal stability)

Better organoleptic properties (taste masking)

Increased patient compliance (decreased side effects)

Modified release dosage forms

There are several factors that are needed to be considered while selecting appropriate salt
form. The main factor that determines the appropriate salt form is type of formulation that is to
be developed.

Mostly, sodium and hydrochloride are the most suitable forms to be used if formulation to be
developed is tablet, oral solution, or injectable. With sodium and hydrochloride as salt form,
there is always enhanced solubility and hence better bioavailability is assured. For example, the
propionic acid derivative naproxen exists in free acid form and has lower water solubility and
hence less bioavailability. When it is converted to sodium salt, its water solubility is increased
by several fold and hence better bioavailability is assured. Similarly, tolbutamide, an oral
hypoglycemic agent has 1000-fold greater water solubility than corresponding free acidic form.

Another factor that determines the type of salt form is type of formulation to be developed. For
example, when the formulation to be developed is suspension, insoluble salt forms like tosylate,
estylate, and embonate are the preferred salt forms.




Therapeutic indication is another factor that affects the selection of salt form. For example, if
drug is indicated in the treatment of hypertension, the use of sodium or potassium salt is
avoided. This is the main reason behind development of potassium salt of diclofenac, which is
preferred over sodium salt. Diclofenac potassium can be given as analgesic in patient with
history or current occurrence of hypertension.

As the regulatory perspective, selection of salt form must meet regulatory requirements and
must be free from toxicity. For example, use of lithium salt is strictly prohibited.

For immediate release formulations, generally sodium or hydrochloride salts are preferred as
they show better solubility. For delayed release formulation, one can prefer low solubility salt
form such as tosylate, estylate, and embonate.

Increased patient compliance can be obtained by converting a molecule to a salt form. For
instance, injection of cephalosporin generates the pain at site of application. However, when it
is administered as morpholine salt, the pain at the site of application was reduced to many
folds. In similar way, salt form can improve the taste adaptability by masking the taste and odor.
Piperazine can be improved organolaptically by converting into salt with adipic acid.

2. Prodrug:

Prodrug is the chemically modified inactive derivative of active form with optimized properties
and better in vivo performance. Almost one-tenth of the pharmaceutical products are used as
prodrug with main aim of improving bioavailability by avoiding first-pass metabolism, improved
drug absorption, and organ selective transport. So prodrug can be defined as inactive form that
undergoes biotransformation and converted to active form to elicit its pharmacological effect.
Development of prodrug depends on specific property of drug that needs improvement and
mostly with respect to stability, improving bioavailability .

In recent times, science has moved to “cod drugs,” “hard drugs,” and “soft drugs,” where cod
drug consists of two pharmacologically active components, which are complexed to form a
single molecule (e.g., sulfasalazine, Levodopa-Entacapone). Soft drugs are the modified
derivatives with predetermined metabolism, so that after exerting pharmacological action for
suitable time, its metabolite can be eliminated from body. Main aim of developing soft drugs is
to avoid toxicity associated with formed metabolites. Hard drugs are opposite to soft drugs,
where the modifications are made in such a way that its original properties are retained but are
not prone to chemical or biological transformation to avoid generation of metabolites or to
increase the biological activity.




Apart from abovementioned classification, there are two main broad classes of prodrug that
are carrier-linked prodrug and bio precursor prodrug. In carrier-linked prodrug, the drug is
linked to a carrier moiety by a temporary covalent linkage. Cleavage of a carrier prodrug
generates a molecular entity of increased bioactivity (drug) and at least one side product, the
carrier, which may be biologically inert. Carrier molecule or functional group can be easily
removed in vivo, usually by hydrolytic cleavage . There are several criteria for being a carrier-
linked prodrug, which are as follows:

Link between drug and a carrier molecule must be a covalent linkage.

Carrier-linked prodrug is inactive or less active than the parent compound.

The linkage between the drug and the carrier molecule must be broken in vivo.

The prodrug, as well as the in vivo released transport moiety, must be nontoxic.

The generation of the active form must take place with rapid kinetics to ensure effective drug
levels at the site of action and to minimize either alternative prodrug metabolism or gradual
drug inactivation.

Bio precursor prodrug results from a molecular modification of the active principle. In vivo
transformation of drug generates a new metabolite .

Several goals of developing prodrug are as follows:

Improving unfavorable physical properties:

Improvement in water solubility.

Improvement in lipophilicity.

Improvement in chemical stability.

Improvement in organoleptic characteristic.

Improving unfavorable pharmacokinetic properties:

Improving bioavailability.

Improving penetration power through membrane.

Improved first-pass metabolism.

Target-specific drug delivery:

Classical example of target-specific drug delivery in selective metastatic colon cancer is
capecitabine which is prodrug of 5-fluorouracil. Capecitabine requires triple-phase




transformation to be converted to its active form 5-fluorouracil. The first metabolism takes
place in liver by action of enzyme carbonyl esterase. This transformed form then enters the
tumor cells by selective uptake and is again transformed by deamination by action of enzyme
cytidine deaminase. This form in tumor cell is converted to 5-fluorouracil by enzyme thymidine
phosphorylase, which is only present in the tumor cells.

The other example of target-specific delivery is release of sulfasalazine in colon by action of
bacterial reductase where sulfasalazine is converted to sulfapyridine and 5-amino salicylic,
where the later formed is the active molecule.

Determination of chemical properties:

Determination of chemical properties indicates the absorption behavior as well as stability of a
molecule in the body. One of the most widely determined chemical properties includes
partition coefficient (Log P), dissociation constant (pKa or pKb), and stability of molecule under
a variety of conditions. Each property has significant value in development of formulation.

1.Partition coefficient:

Partition coefficient (Log P) value is defined as ratio of unionized drug distributed between
aqueous and organic phase. Oil-water partition coefficient gives the idea about drug’s ability to
cross the lipid membrane. Lipophilic/hydrophilic balance is one of the most important
contributing factors for optimum drug absorption and delivery. Due to lipid nature of biological
membrane, the amount of drug absorbed depends heavily on its lipophilicity. It is the unionized
form of molecule that has better lipophilicity and hence it has received so much importance.


If the value of Log P is 0, it indicated that drug has equal distribution in water and partition
solvent. Value of Log P less than 1 is indicative of higher water solubility and value greater than
1 is indicative of higher lipid solubility. For optimum solubility and absorption, a proper
hydrophilic-lipophilic balance is necessary.

Determination of Log P value in biological system is next to impossible task, so several methods
are available to determine partition coefficient of molecule in vitro, which are as follows:

 Shake flask method

 Chromatographic method (HPLC)

 Computation based on software

 Countercurrent/filter probe method




Highly used method is shake flask method that utilizes octanol-water system to determine
drug’s partitioning behaviors. There are several reasons behind selection of octanol as
partitioning solvent, which can be explained as follows:

Octanol is believed to mimic the lipoid character of biological membrane as it contains polar
head and nonpolar tail. Octanol is organic compound that is immiscible with water; however,
some of the water is expected to be present in polar head portion. Solubility parameter for
most of the drugs resembles with that of octanol.

2.Dissociation constant:

Like partition coefficient, dissociation constant (pKa) is the property that determines the
solubility in pH-dependent environment and extent of ionization. It is the extent of ionization
that determines the absorption as only unionized form can be absorbed and hence it becomes
essential to determine the pKa value of molecule. pKa value determination gives idea about site
of absorption.

Weakly acidic drugs having pKa value around 4 are best absorbed from stomach as they are
predominantly present in unionized form. Basic drugs having pKa value of around 8 are best
absorbed from intestine as they are predominantly present in unionized form. % ionization can
be determined by the following equation:


Most of the strong acids and strong bases are present in ionized form throughout GIT and
hence poorly absorbed. But it is also true that most of the pharmaceutical entities are
derivatives of weak acids and weak bases and hence absorption is not an issue.


One of the most silent chemical parameters that define the pharmacological activity is the type
of isomer. Many molecular entities exist in racemic form, but only one form gives the desirable
pharmacological activity. Other present isomer may be devoid of pharmacological activity or
may exhibit deleterious side effects. Most of us are known to teratogenic tragedy of
thalidomide. Thalidomide exists as racemic form. Racemates contain equal amount of
enantiomer, which are known as either levorotatory (−) or dextrorotatory (+) based on its
ability to rotate the plane of polarized light .

Stability of molecule :

The main objective of determining stability of molecule is to identify the conditions in which
molecule is susceptible to deteriorate and to determine degradation pathway. The mechanism




of degradation and condition provides the idea about proper designing of formulation, suitable
molecular modification, appropriate storage condition, and selection of proper packaging
material. The major mechanisms by which a molecule undergoes degradation are hydrolysis,
oxidation, photolysis, and racemization. Out of these mechanisms, hydrolysis is perhaps the
most studied after oxidation.

A.Hydrolysis : Hydrolysis involves reaction of a molecule with water resulting in cleavage of a
chemical bond within the molecule. If readily hydrolysable functional groups are available, then
reaction proceeds even at faster rates, making the molecule ineffective. Molecules containing

esters and amide functional groups are prone to hydrolysis and especially the ester derivatives,
which may lead to formation of carboxylic acid or an alcohol.

Effectiveness of molecule therefore depends on hydrolytic stability of molecule. For example,
lidocaine is amide derivative of procaine, which is ester derivative used as local anesthetic. As
ester derivative is more readily hydrolyzed; its duration of action is short while amide derivative
is more stable and hence used as long-acting local anesthetic.

Beta-lactam antibiotics are susceptible to hydrolysis and hence they are supplied as dry powder
injection where they are reconstituted before intravenous administration.

B. Oxidation :

Many molecules can undergo oxidative degradation, which involves exposure of molecule to
atmospheric oxygen or autoxidation by free radicals. However, in some cases, oxidation can be
initiated in presence of light or elevated temperature. So degree of oxidation can be controlled
by avoiding exposure to lights and storage at controlled temperatures. Even the extent of
oxidation can be controlled by addition of antioxidants. The extent of oxidation for a given
substance can be studied by passing oxygen through the solution of substance, or it can be
achieved by addition of hydrogen peroxide to the solution of substance.

C . Photolysis :

Photolysis refers to decomposition of a molecule by absorption of energy when exposed to light.
Exposure to light not only brings photo degradation but may trigger oxidation. It is absorption
of shorter wavelength components that may bring oxidation than longer wavelength
components. Prior knowledge of photochemical behavior can provide guidance regarding
storage condition, packaging, and handling condition. In most of the cases, the photochemical
behavior of molecule is studied in the range of different spectral regions that are 200–290,
290–320, 320–400, and 400–700 nm. For example, riboflavin and vitamin B12 are susceptible to




photo degradation directly and oxidation induced by light. So to avoid the decomposition, the
formulation containing vitamin B12 and riboflavin is stored in amber color vials. Amber color
bottles do not allow the ultraviolet radiation to pass through, which is the main factor for photo
degradation .

D. Racemization :

It is an event where optically active molecule becomes inactive without any change in
molecular composition. Such study is of highest importance when racemic mixture form is used.
Racemization leads to either loss of pharmacological action or toxic effect may be enhanced by
several fold. Racemization is mostly affected by the conditions like pH, type of solvents,
presence of light, and temperature. So main goal in this study is to design optimum condition in
which molecule can remain stable

Physical characterization of molecule :

A .Solubility

One of the most widely studied techniques during preformulation analysis is solubility profile of
drug candidate. It is the backbone study of preformulation stage that determines the
performance of developed formulation. Solubility and permeability forms the scientific basis of
bio pharmaceutics classification system (BCS), which can provide framework for designing type
of drug delivery system.



There are several techniques, which are available to improve the solubility of drug candidate,
which are as follows:

 Chemical modification of drug

 Addition of cosolvent or surfactant

 Particle size reduction




 Hydrotropy

 Complexation

B. Crystalline vs amorphous form :

Amorphous drugs have randomly arranged molecules or atoms in the molecular lattice. Typical
amorphous forms are obtained by techniques like precipitation, rapid cooling after melting, and
lyophilization. One of the most important advantages associated with amorphous form is the
higher solubility and hence the higher dissolution rate. More often than not drugs with low
water solubility lead to poor bioavailability and variable clinical response. So, polymorphic form
may overcome this problem with main challenge of stability. The associated disadvantage is the
reduced stability in comparison to crystalline form, so upon storage, amorphous forms tend to
revert to more stable form. But the risk-to-benefit ratio remains in the favor of amorphous
from and hence is more preferred for product development. For example, novobiocin when
administered in crystalline form showed no therapeutic activity, while amorphous from showed
better absorption from gastrointestinal tract with significant therapeutic response . Crystalline
form is characterized by regular spacing between molecular lattices in three-dimensional
structure. One of the striking advantages associated with this form is the impeccable stability at
a cost of lower water solubility than amorphous form. For example, Penicillin G as sodium or
potassium salt in crystalline form has the better stability and hence stable and better
therapeutic response in comparison to amorphous form. Various techniques are available to
study crystallinity like X-ray, differential scanning microscopy, differential thermal analysis, hot
stage microscopy, and the most important one that is scanning electron microscopy.

C. Polymorphism and pseudo polymorphism :

Polymorphism is the ability of a compound to crystallize as more than one distinct chemically
identical crystalline species with different internal lattices or crystal packing arrangement. Type
of crystalline species generated depends on temperature, solvent, and time. Polymorphs are
chemically same but mainly differ with respect to physical and pharmaceutical properties. As
different types of polymorphs exhibit different types of solubility, stability, and therapeutic
activity, it has become mandatory to have preliminary and exhaustive screening to identify all
the polymorphic crystal forms for each drug. Similarly, chloramphenicol palmitate exists in
three different polymorphic forms, namely, A, B, and C. Form B has higher solubility and better
dissolution profile, while form A is more stable one but low serum concentration was observed.
During formulating suspension of an anthelmintic drug oxyclozanide, transformation of
unstable polymorph to more stable leads to different crystal size and causes caking. In case of
creams, crystal growth leads to gritty texture and incase of suppositories one can observe
different melting behaviors and leads to formulation instability .




When solvent molecules are incorporated into structure of drug molecule, it is known as
solvate. When water is incorporated as solvent in the structure, they are termed as hydrates.
Pseudo polymorphs are the different crystal form of solvates. This phenomenon is also referred
to as solvomorphism. For example, during synthesis of ethinylestradiol, crystallization of final
product is achieved by using solvents like acetonitrile, chloroform, methanol, and water. As a
result, four different solvates are generated. Differentiation of pseudo polymorphs can be
studied by hot stage microscopy (melting behavior). True polymorphs melt slightly and form a
globule, while pseudo polymorphs give bubble in the system due to generation of vapor or gas
from entrapped solvent.

Two different types of polymorphs are well defined and are known as “monotropic
polymorphs” and “enantiotropic polymorphs.” Monotropic polymorph can be reversibly
changed into another form by change in temperature and pressure and the latter involves one-
time transition into another form. With respect to stability and solubility, again polymorphs can
be classified as stable and metastable polymorphs. Stable polymorph is one of the most
physically stable polymorphic forms and has highest melting point, lowest energy, and least
aqueous solubility, while metastable polymorph refers to forms other than stable polymorph
and has highest energy, low melting point, highest aqueous solubility, and hence shows better
bioavailability. Metastable polymorphs have wider application in developing formulation but
still only one-tenth of metastable forms are having practical use as they suffer from the stability
issues .

D. Deliquescency vs. hygroscopicity :

Hygroscopicity can be defined as the capacity of a compound to absorb atmospheric moisture.
Amount of moisture absorbed depends on atmospheric conditions and surface area.
Deliquescent substance absorbs moisture to a greater extent and liquefies itself. The main
reason behind study of this property is because changes in the moisture level can influence
chemical stability, flowability, and compressibility to a greater extent.

In European pharmacopeia, hygroscopicity is described by four different classes after being
stored at 25°C at relative humidity of 80% for 24 hours.

Slightly hygroscopic: After abovementioned storage condition, if overall increase in weight is
greater or equal to 0.2% but less than 2% w/w.

Hygroscopic: After abovementioned storage condition, if overall increase in weight is greater or
equal to 0.2% but less than 15% w/w.

Very hygroscopic: After abovementioned storage condition, if overall increase in weight is
greater than 15% w/w.




E. Particle size ;

Particle size greatly affects a number of quality parameters like dissolution rate, solubility,
bioavailability, content uniformity, and lack of grittiness. Application of particle size study
during preformulation stage is described as follows:

 When solubility is major issue, one may significantly improve the solubility by reducing
the particle size (increased surface area).

 In case of suspension, particle size is the most important parameter, which determines
the stability and quality of formulation. Too much reduction in the particle size leads to
generation of charged particle and hence unstable system. On other hand, larger
particle size leads to caking.

 Due to nonuniform particle size distribution, there is significant risk associated with
content uniformity in case of potent formulations.

A number of methods are available to determine particle size, which are as follows:

 Microscopy

 Sedimentation rate

 Coulter counter method

 Surface area determination by nitrogen adsorption method

F.Density and porosity:

Density can be defined as ratio of mass of a substance to its volume, which greatly depends on
particle size distribution and shape. The main problem arises during determination of bulk
volume is the voids, which can be interparticulate, open, and closed intraparticulate. So by
considering the presence of different types of void volume, various densities are proposed.

Following problems can be addressed related to density:

 With drugs having low density, the bulk becomes more and hence capsule formulation is
quite difficult to formulate as capsule can incorporate limited volume.

 In development of tablet formulation, low-density drug creates difficulties as they are
having low compressibility and hardness in tablet is difficult to achieve.

 If the difference of density is more between drug substances and excipientis more,
homogeneity in the formulation is difficult to achieve.




Drug excipient compatibility:

Excipients are added along with the active pharmaceutical ingredient in formulations. Most
excipients possess biological activity but having role in administration, mediating the release of
the active component, and providing stability against degradation. However, inappropriate
excipients can also give rise to inadvertent and/or unintended effects, which can affect the
chemical nature, the stability, and the bioavailability of the API, and consequently, their
therapeutic efficacy and safety. So study about interaction between active ingredient and
inactive ingredient can provide idea about type of incompatibility and the justification behind
the inactive ingredient selection.

 Change in organoleptic properties of formulation.

 Changes in in vivo performance of formulation, that is, dissolution.

 Decreased potency of active ingredient.

 Generation of toxic degradation product.

 Change in physical appearance of formulation, that is, color, phase conversion.

In general, one can say that drug-excipient incompatibility may result in change in physical,
chemical, microbiological, or therapeutic properties of formulation.

1. Physical incompatibility:

In such an instance, active pharmaceutical ingredient and excipients interact without
undergoing changes involving like breaking or formation of new bonds. The resulting drug
product retains its original chemical properties but may involve changes such as alteration in
physical properties. Such interaction results in changes like change in color, odor, flow
properties, and sedimentation rate. Such an example of physical incompatibility is between
tetracycline and calcium carbonate. It results in formation of insoluble complex with calcium
carbonate, leading to slower dissolution and decreased absorption in the gastrointestinal tract.

2. Chemical incompatibility

In such incompatibility, there is interaction of active pharmaceutical ingredient and excipient
through chemical degradation pathway. The chemical reaction involves bond breakage or new
bond formation to produce an unstable chemical entity. Chemical reaction may take place as
hydrolysis, oxidation racemization, and Millard reactions. The resulting changes are more
deleterious than physical incompatibility. This type of incompatibility can be assessed by




chromatographic studies. One of the classical examples of chemical incompatibility is exhibited
by reaction of lactose with amino group of active pharmaceutical ingredient referred to as
“Maillard reaction” and results into darkening of formulation with characteristic odor. Classical
example is of a bronchodilator aminophylline, in which ethylenediamine moiety is reduced by
lactose and as a result brown discoloration appeared in samples containing 1:5 (w/w) mixtures
of aminophylline and lactose after storing at 60°C for 3 weeks .

3. Therapeutic incompatibility

Such interaction is also referred to as biopharmaceutical interaction, but it differs from
previously discussed incompatibilities in a way that interaction will take place once the
formulation is administered into the body. Such type of incompatibility is associated with
alteration in drug absorption in the body. In other way, one can say that interaction is taking
place between excipient, active component, and physiological fluid. One of the classical
examples of such incompatibility is interaction of enteric coated polymers, when administered
along with antacids. In such an event, they dissolve prematurely and release the drug that is
liable to acid degradation or may cause adverse effect in GI, that is, gastric bleeding associated
with NSAIDs.

There are specific methods that are employed to determine the existence of incompatibility
between excipient and the active pharmaceutical ingredient. Out of all analytical techniques,
thermal methods of analysis can provide most positive outcome. In association with thermal
methods of analysis, spectroscopic techniques like X-ray diffraction and infrared spectroscopy
can provide sideline assistance. High-performance liquid chromatography and thin-layer
chromatography provide the more suitable way of studying chemical incompatibilities and
provide qualitative and quantitative assessments.

It can be concluded that preformulation is a proactive phase that deals with transformation
of new chemical entity into a safe, effective, and most importantly stable pharmaceutical