Most of the materials used in pharmacy and pharmaceutical industry occur as finely divided solid materials, known as powders. Understanding the origin and nature of these powders is important for their effective usage.
Production of
powders and granules
Most
of the materials used in pharmacy and pharmaceutical industry occur as finely
divided solid materials, known as powders. Understanding the origin and nature
of these powders is important for their effective usage.
Powdered
raw materials for pharmaceutical applications can be of natu-ral, synthetic, or
semisynthetic origin. This is exemplified by the common excipients used in
pharmaceutical manufacturing. For example1:
·
Natural origin: animal products
Lactose is produced from the whey of cows’ milk, whey being
the residual liquid of the milk following cheese and casein produc-tion.
Lactose is a commonly used fragile and water-soluble filler.
·
Natural origin: plant products
Microcrystalline
cellulose is manufactured by the controlled hydro-lysis, with dilute mineral
acid solutions, of α-cellulose,
which is obtained as a pulp from fibrous plant materials. Following hydrolysis,
the hydrocellulose is purified by filtration, and the aque-ous slurry is spray
dried to form dry, porous particles of a broad-size distribution.
Microcrystalline cellulose is commonly used as plastic deformable filler.
·
Starch is extracted from plant sources through a sequence of
process-ing steps involving coarse milling, repeated water washing, wet
siev-ing, and centrifugal separation. The wet starch obtained from these
processes is dried and milled before use in pharmaceutical formu-lations.
Starch is used as a filler, binder, and disintegrant in tablet formulations.
·
Pregelatinized starch is chemically and/or mechanically
processed starch that possesses better flow, compressibility, and binding
properties.
·
Semisynthetic
product
Sodium starch glycolate is a substituted and cross-linked
deriv-ative of potato starch. Starch is carboxymethylated by react-ing with
sodium chloroacetate in an alkaline medium followed by neutralization with
citric, or some other acid. Cross-linking may be achieved by either physical
methods or chemical methods by using reagents such as phosphorus oxytrichloride
or sodium trimetaphosphate. Cross-linking hydrophilic polymer chains cre-ates
an excipient that swells but does not dissolve in the presence of water and can
serve as a tablet disintegrant.
·
Hydroxypropyl cellulose (HPC) is water-soluble cellulose
ether pro-duced by the reaction of cellulose with propylene oxide. This is a
long chain hydrophilic polymer that serves as a binder in wet granulation.
·
Synthetic product
Pyrrolidone is produced by reacting butyrolactone with
ammonia. This is followed by a vinylation reaction in which pyrrolidone and
acetylene are reacted under pressure. The monomer, vinylpyrrol-idone, is then
polymerized in the presence of a combination of cat-alysts to produce
polyvinylpyrrolidone, also known as povidone. Povidone, a long chain
hydrophilic polymer, is also a commonly used binder in wet granulation.
·
Water-insoluble cross-linked polyvinyl pyrrolidone (PVP,
crospovi-done) is manufactured by a polymerization process, where the cross-linking
agent is generated in situ.
Cross-linking of the hydrophilic polymer generates a swellable but insoluble
polymer that serves as a disintegrant.
·
Magnesium stearate is prepared either by chemical reaction
of aque-ous solution of magnesium chloride with sodium stearate or by the
interaction of magnesium oxide, hydroxide, or carbonate with stearic acid at
elevated temperatures. Magnesium stearate is a fine hydro-phobic powder that
serves as a lubricant in the manufacture of solid dosage forms.
Most
of the drug substances are of synthetic origin. A chemical synthesis process is
preferred over natural raw materials to assure adequate material purity,
availability, and consistency of the process. Few drug compounds, such as
taxol, are of semisynthetic origin. Most drugs are purified as pure powder
crystals at the end of their synthesis. In the case of amorphous drugs,
processes such as lyophilization and spray drying are used to con-vert the
drugs into solid forms for purification, long shelf life, and ease of handling.
Crystalline APIs are preferred because they are more stable, and the process of
crystallization removes non-API molecules, such as intermediates used during
synthesis, from the crystal lattice—thus ensur-ing purity.
The
powders used in pharmaceutical industry and pharmacy practice could be either
crystalline or amorphous in nature.
·
Crystalline powders have a well-defined and repeating,
long-range order of the arrangement of molecules due to intermolecular
interac-tions in the solid state. The term long
range indicates that many mol-ecules may be involved in the intermolecular
interactions that define the fixed arrangement of molecules in a crystalline
structure. This smallest fixed arrangement of molecules that repeats throughout
the crystal is known as a unit cell. In a crystalline material, the
arrange-ment of molecules with respect to each other is well defined and not
random.
·
Amorphous powders do not have a well-defined and repeating,
long-range order of the arrangement of molecules. The molecules of an amorphous
solid may show intermolecular interactions, but these interactions may not
repeat consistently over several molecules. Therefore, in an amorphous material,
the orientation of molecules with respect to each other is largely random.
Most
of the APIs are crystalline in nature and are produced by a process known as
crystallization.
Crystallization
is the production of solid crystals in a solution of the solute being
crystallized, which is followed by the subsequent separation of those crystals
from the solution. Crystallization is accomplished by creating a state of
supersaturation of the solute in a solution. A supersaturated solu-tion has a
solute concentration greater than the thermodynamic equilib-rium solubility of
the solute in the solvent.
Supersaturation
can lead to crystallization through the spontaneous for-mation or extraneous
addition (seeding) of nuclei. Nuclei are the associa-tions of few (10s to 100s)
molecules with the same intermolecular spatial arrangements that characterize
the crystal form. Supersaturation can be achieved in one of several ways:
·
Evaporation of solvent from a solution.
·
Changing the temperature of the solution. For example,
cooling the solution could lead to supersaturation if the solute has a positive
heat of solution (increase in solubility with increase in temperature).
·
Production of additional solute in the solution by chemical
reaction.
·
Change in solution by the addition of other soluble
solute(s).
·
Change in solution by the addition of other solvent(s). For
example, addition of a miscible solvent that has lower solubility for the
solute could lead to the formation of a cosolvent system with lower overall
solute solubility than the solute concentration.
The
crystals of a solute in its solution can undergo either of the two
processes—growth of the crystals involving transfer of solute from the solution
to the crystal state (crystallization) or loss of solute molecules from the
crystals into the solution (dissolution). Crystallization would be expected in
the case of supersaturated solutions, and dissolution of the crystals is
expected when the solution concentration is lower than the sat-uration
concentration.
Although
the driving forces for these processes (relative strength of solute– solute,
solute–solvent, and solvent–solvent interactions) are the same, they can have
very different rates for the same concentration gradient. Generally, the rate
of dissolution is greater than the rate of crystallization.
Polymorphism
refers to the ability of a solid to exist in more than one crystal structure or
form. Intrinsic properties of a molecule together with crystallization
conditions determine the possibility of existence of dif-ferent crystalline
(polymorphic) or amorphous forms of a molecule. For example, certain molecules
may only exist in one form in the solid state. Some other molecules can have several
crystalline forms and may also exist in an amorphous state. For example,
flufenamic acid exists in nine different polymorphic forms.
Polymorphism
can be of different types depending on the driving forces or the underlying
molecular reason for polymorphism:
· The existence of polymorphism due to differences only in the
spatial arrangement of molecules in a crystal, or crystal packing, is termed
packing polymorphism.
· When a solute can exist in different crystal types depending
on its state of solvation or hydration, the polymorphism is termed
pseudopolymorphism.
· Polymorphism attributable to different conformers of a
molecule, formed by rotation along single bond(s), is known as conformational
polymorphism.
At
a molecular level, polymorphs differ in the strength and nature of
intermolecular interactions. Polymorphs differ in the surface exposure of
functional groups of the molecule on different faces of a crystal. Accordingly,
different polymorphic forms of a molecule usually differ in their surface properties
such as wettability and interparticle interactions leading to differences in
dissolution rate, bioavailability, and/or chemical stability.
Changing
the conditions of crystallization can generate spatial poly-morphs. For
example, type of solvent, degree of supersaturation, pH of solution, rate of
cooling, extent of mixing, or the presence of impurities in solution can lead
to the formation of different crystalline forms of a molecule. Seeding the
solution with a small quantity of the desired crys-tal form generates the same
crystal form.
Crystalline
forms have lower free energy and are thermodynamically more stable than
amorphous forms of a molecule. Thus, an amorphous form tends to convert to a
crystalline form on storage.
Different
crystalline polymorphic forms usually differ in their thermo-dynamic stability.
When a drug substance exists in different polymor-phic forms, the greater
thermodynamic stability of one crystalline form over another is often
attributable to the higher strength of intermolecu-lar interactions and/or
closer or dense crystal packing. These differences often reflect in the melting
point of various crystalline forms. Thus, the higher melting crystal form is
usually also the more stable form.
A
metastable (less stable) polymorphic form tends to transform into a more stable
polymorphic form on storage. A change in the polymorph of an API during
pharmaceutical manufacturing or in a finished drug prod-uct can lead to
unintended consequences with respect to drug stability or bioavailability.
Therefore, identification and characterization of poly-morphic forms of a drug
substance are carried out during new product development. In addition, the
thermodynamically most stable polymor-phic form is usually preferred for use in
a drug product.
Amorphous
forms of a solute can be produced by several means. For example, a high rate of
solvent evaporation from a solution of the solute can result in the
precipitation of solute in an amorphous form. High rate of solvent evaporation
can be achieved, for example, by spray dry-ing. Spray drying involves
atomization of a solution followed by solvent evaporation in a continuous flow
gaseous phase at a temperature higher than the boiling point of the solvent.
Large evaporating surface area of small droplets of solution facilitates the
rapid rate of solvent evaporation. Changes in process parameters for spray
drying, for example, droplet size, solute concentration, and rate of solvent
evaporation can lead to significantly different powder properties, such as
size, of the precipitated material.
Solvent
removal from a solution is also utilized to generate powders that contain two
or more solid substances intimately mixed together in a fixed composition. This
process generates powder particles that have one solid dispersed or dissolved
in another solid of higher quantity. These systems are termed solid dispersions
or solid solutions, respectively. These systems can be utilized to generate and
stabilize amorphous forms of a drug substance. The choice of the other
component (non-API or excipient) in these systems can determine the stability
and dissolution rate of a drug from its solid dispersion or solid solution.
Commonly used hydrophilic excipients that are used to prepare stable amorphous
solid dispersions of APIs include povidone and hydroxypropyl methylcellulose
acetate succinate (HPMC-AS). Use of hydrophobic excipients, such as Eudragits®,
can produce solid dispersions with slow or sustained drug release properties.
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