Most pharmaceutical companies would rather have their new molecule enter the market as a tablet or capsule for a variety of safety, cost, and marketing considerations. As a result, almost 70% of all drugs administered today are in solid dosage forms. When so intended and the default form should be solid dosage form (unless it is predetermined in the case of therapeutic proteins or other drugs that must be administered by parenteral route or other specific routes for specificity of activity desired. The typical parameters studies for solid dosage forms relate to the ability of a powder mix, to flow well in manufacturing machines, as well as to the intrinsic characteristics that make it compressible. Some examples of properties studied include: crystal structures (polymorphs), external shapes (habits), compression properties, cohesion, powder flow, micromeritics, crystallization, yield strengths and effects of moisture and hygroscopicity, particle size, true, bulk and tapped density, surface area.
The particle size of new drug substance is a critical parameter as it affects every phase of formulation and its effectiveness. Appropriate particle size is required to achieve optimal dissolution rate in solid dosage forms, control sedimentation, and flocculation in suspensions, small particle size (2-5 nm) is required for inhalation therapy, content uniformity and compressibility is governed by particle size. As a result, the preformulation studies must develop a specification of particle size as early as possible in the course of studies and develop specifications that need to be adhered to throughout the studies.
Conventional methods of grinding in mortar or ball milling (where sample quantity is sufficient; generally it is not and limited to about 25-100 mg) or micronization techniques are used to reduce the particle size. The method used can have significant effect on the crystallinity, polymorphic structures (often to amorphous forms) and drug substance stability that can range from discoloration to significant chemical degradation. Changes in polymorphic forms can be determined by performing X-ray powder diffraction (XRPD) before and after milling.
Micronization where possible allows increase in the surface area to the maximum which can impact on the solubility, dissolution and as a result, bioavailability. Since the aim of most preformulation studies is to determine if a solid dosage form can be administered, knowing that reduction of particle size where it changes dissolution rates can be pivotal in decision making for the selection of dosage forms. In the process of micronization, the drug substance is fed into a confined circular chamber where it is suspended in a high-velocity stream of air. Interparticulate collisions result in a size reduction. Smaller particles are removed from the chamber by the escaping air stream toward the center of the mill where they are discharged and collected. Larger particles recirculate until their particle size is reduced. Micronized particles are typically less than 10 |im in diameter. In some instances micronization can prove counterproductive, where it results in increased aggregation (leading to reduced surface area) or alteration of crystallinity, which must be studied using such methods as microcalorimetry, dynamic vapor sorption (DVS) or inverse gas chromatography.
The introduction of DVS in 1994 revolutionized the world of gravimetric moisture sorption measurement, bringing outdated, time and labor intensive desiccator use into the modern world of cutting-edge instrumentation and overnight vapor sorption isotherms. With a resolution down to 0.1 |ig, 1% change in mass of a 10 mg sample on exposure to the humidity controlled gas flow is both easily discernable and reproducible. DVS is a valued tool for studies related to polymorphism, compound stability, bulk and surface adsorption effects of water and organic vapors. The DVS studies would typically show percent mass increases but often a hysteris loop relationship is observed where there is crystallization of compound that results in the expelling of excess moisture. This effect can be important in some formulations, such as dry powder inhaler devices since it can cause agglomeration of the powders and variable flow properties. The DVS is useful study when amorphous forms are involved upon size reduction; in many cases, a low level of amorphous character cannot be detected by techniques such as XRPD; microcalorimetry can detect less than 10% amorphous content (the limit of detection is 1% or less). The amorphous content of a micronized drug can be determined by measuring the heat output caused by the water vapor inducing crystallization of the amorphous regions.
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