Production of powders and granules

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.

Origin of powdered excipients

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.

Origin of powdered active pharmaceutical ingredients

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.

Amorphous and crystalline powders

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.

Production of crystalline powders

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.

Crystallization versus dissolution

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

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.

Production of amorphous powders

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.