Preformulation studies characterize the physical, chemical, and mechanical properties of new drug substances to aid in developing stable, safe, and effective dosage forms. Key goals are to establish physicochemical parameters, kinetic rate profiles, physical characteristics, and compatibility with excipients. This helps with dosage form selection and rational design, understanding process variables, and developing bioavailable dosage forms. Principal areas of study include bulk characterization, solubility analysis, stability analysis, and drug-excipient interaction studies to detect incompatibilities. Common interaction types are physical, chemical, and therapeutic.

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PREFORMULATION STUDIES

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Definition
Preformulation may be described as a
phase of the research and development
process where the preformulation scientist
characterizes the physical, chemical and
mechanical properties of a new drug
substance, in order to develop stable, safe
and effective dosage form.

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• To establish the necessary physicochemical parameters of a new
drug substance.
• To determine its kinetic rate profile
• To establish its physical characteristics
• To establish its compatibility with excipients
Significance in formulation development
• Dosage form selection,rationalization and formulation design
• Suitable dosage form development and rationalization
• Understanding the underlying process control variables
• Bioavailable dosage form development
• Efficient process monitoring control ,validation and continuous
improvement
• Determination of process susceptible to failure upon scale up

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• The following events take place between the birth of a new drug
substance and its eventual marketing (most investigational drug
substances never make it to the marketplace for one reason or another:
– The drug is synthesized and tested in a pharmacological screen.
– The drug is found sufficiently interesting to warrant further study.
– Sufficient quantity is synthesized to:
(a) perform initial toxicity studies,
(b) do initial analytical work, and
(c) do initial preformulation
– Once past initial toxicity, phase I (clinical pharmacology) begins and there is a
need for actual formulations (although the dose level may not yet be determined).
– Phase II and III clinical testing then begins, and during this phase (preferably
phase II) an order of magnitude formula is finalized.
– After completion of the above, an NDA is submitted.
– After approval of the NDA, production can start (product launch).

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• Principal areas of preformulation
• Bulk characterization
 Crystallinity and polymorphism
 Hygroscopicity
 Fine particle characterization
 Powder flow
• Solubility analysis
 Ionization constant – pKa
 pH solubility profile
 Common ion effect – KSP.
Thermal effects
Solubilization
Partition coefficient
Dissolution

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• Stability Analysis
 Stability in toxicology formulation
 Solution stability
 pH stability profile
 Solid state stability
 Bulk stability
 Compatibility

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Drug-excipient interaction studies
• An incompatibility may be defined as “An undesirable
drug interaction with one or more components of a
formulation, resulting in changes in physical, chemical,
microbiological or therapeutic properties of the dosage
form.”
• An incompatibility in dosage form can result in any of
the following changes:
• change in colour/appearance;
• loss in mechanical properties (e.g., tablet hardness)
• changes to dissolution performance;
• physical form conversion;
• loss through sublimation;
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• a decrease in potency;
• increase in degradation products
• Excipient compatibility studies are conducted mainly to
predict the potential incompatibility of the drug in the final
dosage form
• These studies also provide justification for selection of
excipients, and their concentrations in the formulation as
required in regulatory filings
• There fillings has also been an increased regulatory focus
on the Critical Quality Attributes (CQA) of excipients and
their control strategy, because of their impact on the drug
product formulation and manufacturing process which
enhanced due to increasing QbD trend
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• These studies are important in the drug development
process, as the knowledge gained from excipient
compatibility studies is used to:
• Select the dosage form components
• Delineate stability profile of the drug
• Identify degradation products
• Understand mechanisms of reactions
• If the stability of the drug with the excipients are found to
be unsatisfactory, strategies to mitigate the instability of
the drug can be adopted
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Modes of
degradation of
drug
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Hydrolysis
Oxidation
Isomerization
Photolysis

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• Drug-excipients interaction occurs more frequently
than excipient-excipient interaction
• Drug-excipients interaction can be classified as:
1. Physical interactions
2. Chemical interactions
3. Therapeutic interactions
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Physical interactions: Physical interaction is the most common form,
but due to a lack of any chemical changes, it is challenging to detect.
The beneficial role of physical interaction is used to enhance the
solubility profile of the drug,
however unintended interactions are unfavorable to product
performance.
e.g., of physical interaction between an API and an excipient is between
primary amine drugs and microcrystalline cellulose.
When dissolution is carried out in water, a small percentage of the drug
may be bound to the microcrystalline cellulose and not released.
For high-dose drugs, this may not be a major issue, but for low dose
drugs it can lead to dissolution failures.

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• Remedied: Carry out dissolution using a weak electrolyte solution for the
dissolution medium (e.g., 0.05 M HCl).
• Under these revised dissolution test conditions, adsorption onto the
microcrystalline cellulose is very much reduced and 100% dissolution may be
achieved even for low-dose APIs
• Magnesium stearate causes problems such as reduced tablet “hardness” and
dissolution from tablets and capsules.
• Adsorption of drug molecules onto the surface of excipients can render the drug
unavailable for dissolution and diffusion, which can result in reduced
bioavailability
 antibacterial activity of cetylpyridinium chloride was decreased when
magnesium stearate was used as lubricants in tablet owing to adsorption of
cetylpyridinium cation by stearate anion on magnesium stearate particle
 Adsorption of novel k-opoid agonist by microcrystalline cellulose led to
incomplete drug release from the capsules.
 Colloidal silica catalyzed nitrozepam degradation in tablet dosage form, possibly
by adsorptive interactions altering electron density in the vicinity of the labile azo
group and thus facilitating attack by hydrolyzing entities.

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• Phenobarbital forms an insoluble complex with PEG-400 leading to slow
dissolution and decreased absorption.
• Complex of prednisolone with water soluble excipients, exhibits an increased
dissolution, however owing to high molecular weight diffusion through GI
membrane is hampered
• Chemical interactions: involves chemical reaction between drugs and
excipients or drugs and impurities/ residues present in the excipients to form
different molecules
• Chemical interactions are mostly detrimental to the product because they
produce degradation products, different degradation poduct are classified as
in ICH guideline ICHQ3B (R2).
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Chemical Drug-Excipient-Interaction
• Hydrolysis: Esters, amides, lactones, or lactams in the formulation can
undergo hydrolysis in the presence of an aqueous environment
• Such hydrolysis of esters in accelerated by the acidic or basic
environments; an acidic environment can lead this de-esterification to
equilibrium, whereas basic media leads the reaction to completion
• E.g. Eslicarbazepine acetate undergoes chemical hydrolysis at low pH
(pH 1.2) and high pH (pH 10) to form the active form—eslicarbazepine
• Oxidation: Alcohols, aldehydes, alkaloids, phenols, and unsaturated fatty
substances, involves an oxidative mechanism. Such reactions are mostly
accelerated by the presence of oxygen, heavy metals, metal oxides
(fumed titania, fumed silica, fumed zirconia), etc., forming free radicals,
which in turn react with oxygen to form peroxy radicals.
E.g. pyrazolone, undergoes an oxidation reaction during storage at
specific experimental conditions and thereby evolves CO2.
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Maillard reaction with primary amines: This reaction is so named
because this was reported by Louis Maillard to form colored pigments from
sugars and amines.
Primary amines in the formulation with carbonyl compounds, basically reducing
sugars, undergo Maillard reaction, to form Schiff’s base (imine substances) and
finally the Amadori rearrangements
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• In certain chewable products, Maillard reactions occurred between
aspartame and a reducing sugar such as dextrose thereby resulting in
the loss of sweetness. The Amadori products are intensely colored
compounds and thus produce yellow brown discoloration on the
developed product.
• Maillard reaction with secondary amines: Secondary amines
also participate in this Maillard reaction in the presence of reducing
sugars. However, the reaction will not extend beyond the formation of
Schiff’s base
• Thus, following the reaction with reducing sugars, secondary amines
cannot form Amadori or the colored compounds but still can hamper the
pharmacological response of the drugs.
• Maillard reaction of fluoxetine HCl, a secondary amine occurred with
sucrose.
• edivoxetine, a secondary amine, also showed propensity towards
Maillard reactivity in solution phase
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• Michael adduct formation: Michael adduct formation is a nucleophilic
reaction where a nucleophile (e.g., carbanion/primary amine) forms an adduct to
the α,β-unsaturated carbonyl compounds.
• Therefore, primary amines undergo a chemical reaction with double-bonded
chemicals to form Michael adducts (Fig. 11.3). For example, fluvoxamine, a
primary amine, forms Michael adduct product fluvoxamine maleate when
reacted with the maleic acid, where the double bond in maleic acid is attacked
by the amine substance.
• This adduct form is used as a treatment in depressive disorders.
• Similarly, adducts could be possible with excipients include sorbitan monooleate,
sodium stearyl fumarate.
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