Preformulation Studies
Intended
Learning Objectives
At the end of the
lecture, student will be able to
• Explain preformulation and its role played in formulation
development
• Enlist some of the preformulation studies carried out on
drug molecule
• Discuss the importance of properties like partition
coefficient, dissociation constant and chirality
• Describe factors affecting stability of drug molecules
their importance in preformulation with examples
• Explain the importance of solubility determination in
Preformulation studies
• Discuss the importance of crystallinity, density, particle
size and polymorphism in formulation development
• Describe the importance of determining drug excipient
compatibility during the preformulation stages and the methods for the same
Preformulation
and Formulation
Preformulation - Concept
• Almost all drugs are marketed as tablets, capsules or both
• Prior to the development of these major dosage forms, it
is essential that certain fundamental, physical and chemical properties of the
drug molecule and other properties of the drug powder are determined
• This information decides many of the subsequent events and
approaches in formulation development
• This first learning phase is known as preformulation
Preformulation
- Definition
• It can be defined as an investigation of physical and
chemical properties of a drug substance - alone and or when combined with
excipients
Drug
Drug + excipients
Preformulation
– Objectives
• 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 right target
• To provide longer stability to the formulation by proper
designing and protecting drug component from environmental condition and to
evaluate performance of developed formulation
Peformulation
studies on drug molecule
• Partition coefficient (Log P)
• Dissociation constant (pKa or pKb)
• Stability of molecule under a variety of conditions
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 lipidic membrane
• Lipophilic/hydrophilic balance is one of the most important contributing factors for optimum drug absorption and delivery
Partition coefficient
determination
In vitro methods
• Shake flask method
• Chromatographic method (HPLC)
• Computation based on software
• Countercurrent/filter probe method
Shake flask method
• Highly used method is shake flask method that utilizes
octanol-water system to determine drug’s partitioning behaviors
Why Octanol???
• Octanol is believed to mimic the lipoidal 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
Dissociation
constant
• Dissociation constant (pKa) is the property that
determines the solubility in pH-dependent environment and extent of ionization
• Extent of ionization determines absorption
• Only unionized form can be absorbed
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
Partition coefficient and absorption
Chirality
• 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
• Thalidomide exists as racemic form
• It was introduced as a sedative agent
• The S-enantiomer of thalidomide was a teratogenic agent (causes birth defects), while R-enantiomer was effective as a sedative agent
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
• Racemization.
Hydrolysis
• Hydrolysis involves reaction of a molecule with water
resulting in cleavage of a chemical bond within the molecule
• Presence of hydrolyzable functional groups à faster hydrolysis of
the molecule
Functional groups like esters and amide are prone to hydrolysis and especially the ester derivatives
Lidocaine |
Procaine |
• amide derivative |
• ester derivative |
• used as local anesthetic |
• used as local anesthetic |
• more stable and hence used as long-acting local anesthetic |
• more readily hydrolyzed; its duration of action is short |
• Beta-lactam antibiotics are susceptible to hydrolysis
• Hence they are supplied as dry powder injection where they are reconstituted before intravenous administration
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
• 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
• So degree of oxidation can be controlled by avoiding
exposure to lights and storage at controlled temperatures
• The extent of oxidation can be controlled by addition of
antioxidants
Photolysis
• Photolysis refers to decomposition of a molecule by
absorption of energy when exposed to light
• Exposure to light not only brings photodegradation but may trigger oxidation
• Prior knowledge of photochemical behavior can provide
guidance regarding storage condition, packaging, and handling condition
• Example, riboflavin and vitamin B12 are susceptible to
photodegradation 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 photodegradation
Racemization
• It is an event where optically active molecule becomes
inactive without any change in molecular composition
• 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
• Main goal in this study is to design optimum condition in
which molecule can remain stable
Physical
Characterization of Molecules
• Most of the newly discovered drugs are solids
• Properties under study during preformulation phase are
bulk property characterization and micromeritic property characterization
Bulk property
characterization |
Micromeritic
characterization |
• Polymorphism |
• Particle size |
• Crystallinity |
• Shape |
• Density |
• Porosity |
• Deliquescence or hygroscopicity
|
|
Solubility
& Permeability
Solubility
• The solubility of a drug is the amount of the drug that dissolves in a given solvent to produce a saturated solution at constant temperature and pressure
Solubility is not an independent parameter but it relies on
several properties like crystal characteristics, temperature, pH, complexation,
and molecular structure
• Most widely studied techniques during preformulation
analysis is solubility profile of drug candidate
• Solubility and permeability forms the scientific basis of
Biopharmaceutics Classification System (BCS)
• BCS provides framework for designing type of drug delivery
system
Solubility, permeability and type of formulation
Solubility
Improvement Techniques
• Chemical modification of drug
• Addition of cosolvent or surfactant
• Particle size reduction
• Hydrotropy
• Complexation
Crystalline
& Amorphous form
Amorphous |
Crystalline |
|
|
• Amorphous drugs have randomly arranged molecules or atoms in the
molecular lattice |
• Crystalline form is characterized by regular spacing between
molecular lattices in three- dimensional structure |
• Higher solubility and dissolution rate |
• Lower solubility compared to crystalline form |
• Higher stability |
• Lower stability |
Novobiocin when administered in crystalline form
showed no therapeutic activity,
while amorphous from showed
better absorption from gastrointestinal tract with
significant therapeutic
response |
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 |
Techniques to study
Crystallinity
1. Scanning electron microscopy
2. X-ray
3. Differential scanning microscopy differential thermal
analysis
4. Hot stage microscopy,
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
Polymorphic forms -
Significance
• Different types of polymorphs exhibit different types of
solubility, stability, and therapeutic activity
• 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
Deliquescency
& Hygroscopicity
• Hygroscopicity can be defined as the capacity of a compound to absorb atmospheric moisture
• Deliquescent substances absorb atmospheric moisture absorbing to a EXTREME extent and liquefy itself
Why study hygrocopicity?
• Changes in the moisture level can influence
Chemical
stability
Flowability
Compressibility
to a greater extent
• Moisture level uptake can be monitored by techniques like
thermogravimetric analysis (TGA), Karl Fischer titration, and gas
chromatography
Classes of
Hygrocopicity
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.
Particle
Size
• Particle size greatly affects
dissolution rate
Solubility
Bioavailability
content
uniformity
lack of
grittiness
Application of particle
size in preformulation
• 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 non-uniform particle size distribution, there is
significant risk associated with content uniformity in case of potent
formulations.
Particle size
determination
• Microscopy
• Sedimentation rate
• Coulter counter method
• Surface area determination by nitrogen adsorption method
Density -
Issues
• Capsules: With
drugs having low density, the bulk becomes more and hence capsule formulation
is quite difficult to formulate as capsule can incorporate limited volume
• Tablets: In
development of tablet formulation, low-density drug creates difficulties as
they are having low compressibility and hardness in tablet is difficult to
achieve
• Homogeinity: If the difference of density is more between drug substances and excipient is more, homogeneity in the formulation is difficult to achieve
Flow properties
• Efficient flow of drug substance powder is needed for effective tablet formulation
Drug
excipient compatibility
Effects of drug
excipient incompatibility
• 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
Physical
incompatibility
• Such interaction results in changes like change in color,
odor, flow properties, and sedimentation rate
• 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
Chemical
incompatibility
• Chemical reaction may take place as hydrolysis, oxidation
racemization, and Maillard reactions
• 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.
• Bronchodilator aminophylline + lactose à brown discoloration
appeared in samples after storing at 60°C for 3 weeks
Therapeutic
incompatibility
• Interaction will take place once the formulation is
administered into the body
• Example: enteric coated polymers, when administered along
with antacids dissolve prematurely and release the drug that is liable to acid
degradation or may cause adverse effect in GI, that is, gastric bleeding
Determination of drug
excipient incompatibility
• Thermal Analysis
Properties of materials are studied as they change with
temperature
DSC – Differential
Scanning Calorimetry
TGA – Thermo
Gravimetric Analysis
DTA – Differential
Thermal Analysis
• High performance liquid chromatography (HPLC)
• FTIR
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