Pharmaceutics
Study of formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms
is known as Pharmaceutics.
A dosage form is the physical form of a dose of a drug intended for administration e.g. Pill,
tablet, capsule, liquids, aerosol or inhaler, liquid injection, pure powder or solid crystal etc.
Each type of dosage form is unique in its physical and pharmaceutical characteristics.
FORMULATION
Active Pharmaceutical Ingredient (API) is rarely administered solely as pure substance but are
given as part of a formulation in combination with one or more pharmaceutical ingredients or
excipients. Selective use of these excipients produces dosage forms of various types. Though
excipients are defined as therapeutically inactive but it is a well-established fact that they may
interact with the API in the formulation. This interaction reduces the effectiveness of dosage
form. A good excipient must be biocompatible.
Objective of Formulation
To produce a final medicinal product that is stable and acceptable to the patient
Formulation studies
The following studies are conducted prior to formulation:
Selection of Drug
Nearly half of the drug molecules that are marketed as drug products are administered in salt
form. 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. In
similar way, salt form can improve the taste by masking the taste and odor. Piperazine can be
improved organoleptically by converting into salt with adipic acid.
There are several factors that are considered while selecting appropriate salt form. The main
factor is the type of formulation to be developed.
• Mostly, sodium and hydrochloride are the most suitable forms if formulation to be
developed is tablet, oral solution, or injectable. As salt form, there is always enhanced
solubility and hence better bioavailability. For example tolbutamide, an oral
hypoglycemic agent has 1000-fold greater water solubility than corresponding free
acidic form.
• when the formulation to be developed is suspension, insoluble salt forms are the
preferred salt forms.
• 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
Selection of salt form must meet regulatory requirements and must be free from toxicity. For
example, use of lithium salt is strictly prohibited.
I. Chemical Characterization
Determination of chemical properties indicates the absorption behavior as well as stability of a
molecule in the body. Most widely chemical properties includes partition coefficient (Log P),
dissociation constant (pKa or pKb), chirality and stability of molecule under a variety of
conditions.
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 lipidic membrane. Due to lipidic 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.
2. Dissociation constant
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. It becomes essential to determine the pKa
value of molecule. pKa value gives idea about the 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.
• 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.
3. 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 toxic side effects.
Thalidomide exists as racemic form. We know the teratogenic tragedy of thalidomide. It led to
the death of approximately 2,000 children and serious birth defects in more than 10,000
children in 1961. The deformed limbs and defective organs in children whose mothers took
thalidomide during pregnancy as a treatment for morning sickness.
4. 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.
• 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. Beta-lactam antibiotics are susceptible to
hydrolysis and hence they are supplied as dry powder injection where they are
reconstituted before intravenous administration.
• Many molecules can undergo oxidative degradation, which involves exposure of
molecule to atmospheric oxygen or autoxidation by free radicals.
II. Physical & Pharmaceutical characterizations of drug molecule
Most of the new drugs are solids, they exist either as amorphous or in crystalline state having
different stability and solubility.
1. Solubility
One of the most widely studied techniques during preformulation analysis is solubility profile
of drug. For conversion of drug molecule into an effective oral formulation, it must have good
aqueous solubility for better absorption. Solubility is not an independent parameter but it relies
on several properties like crystal characteristics, temperature, pH, complexation, and molecular
structure.
i. 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. 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.
In contrast, 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.
ii. Polymorphism
Polymorphism is the ability of a compound to crystallize as more than one identical crystalline
species with different internal lattices. 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.
2. Deliquescence 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. Changes in the
moisture level can influence chemical stability, flowability, and compressibility to a greater
extent.
3. 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.
Apart from particle size, particle shape plays an important role during preformulation phase as
the shape of particle may influence surface area, flow properties, and compaction force. A drug
particle may exist in different forms like spherical, angular, needle, oval, or rough. It is a well-
accepted fact that a spherical particle has the maximum area and uniform flow property. The
maximum surface area ensures the better solubility. For topical products, irregular particle
shape is more preferred.
4. 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. 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 excipients,
homogeneity in the formulation is difficult to achieve.
5. Flow properties
Efficient flow of drug substance powder is needed for effective tablet formulation. It is linked
with other physical parameters like hygroscopicity and particle size and shape.
• In case of hygroscopic material, flow property of drug tends to deteriorate as the
presence of absorbed moisture increases cohesiveness.
• Irregular particle size and nonuniform shape can also disturb normal flow property of
drug.
6. Drug excipient compatibility
Excipients are added along with the active pharmaceutical ingredient in formulations.
Inappropriate excipients 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.
i. Physical incompatibility
API 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. 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.
ii. Chemical incompatibility
There is interaction of API 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 Maillard
reactions. The resulting changes are more harmful than physical incompatibility.
One of the classical examples of chemical incompatibility is exhibited by reaction of lactose
with amino group of API referred to as “Maillard reaction” and results into darkening of
formulation with characteristic odor.
iii. Therapeutic incompatibility
Such type of incompatibility is associated with alteration in drug absorption in the body.
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.
In general, one can say that drug-excipient incompatibility may result in change in physical,
chemical, microbiological, or therapeutic properties of formulation.
7. Determination of the most appropriate container / closure system
Formulated drugs are stored in container closure systems for extended periods of time. These
include blisters, bottles, vials, ampules, syringes, and cartridges. The containers can be made
from a variety of materials including glass, plastic, and metal. The drug may be stored as a
solid, liquid, or gas. It's important to check whether there are any undesired interactions
between the preparation and the container. For instance, if a plastic container is used, tests are
carried out to see whether any of the ingredients become adsorbed on to the plastic, and whether
any plasticizer, lubricants, pigments, or stabilizers leach out of the plastic into the preparation.
Even the adhesives for the container label need to be tested, to ensure they do not leach through
the plastic container into the preparation.
