Excipient polymorphic forms

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

Plate 8.2 Trace analysis of polymorphic form I of ranitidine. The RGB summary image highlights the distribution of sample components polymorphic form 2 of ranitidine in red, polymorphic form 1 of ranitidine in green and the excipients in blue. 

In other experiments, we have also used this approach with some success to determine the existence and location of low levels of different polymorphic forms within finished products. Plate 8.2 shows an image of a sample containing both polymorphic forms (1 and 2) of the API ranitidine. The overall composition of the tablet is 75% ranitidine (both forms) and 25% excipients. Plate 8.2 highlights the form 1 domains in green, whose abundance is estimated to be -1.2% of the total tablet weight. This information is derived from the analysis of a single tablet. 

FIGURE 11 Example plot of two Raman spectra (two polymorphic forms of an excipient). 

It is essential to understand how and when the polymorphs of drug substance in oral liquid dosage forms and suspensions can be controlled. One approach to study this phenomenon is to seed the formulation with a small amount of a known polymorphic crystal (other than what is used for the product), which is a common practice to rapidly determine what effect this may have on long-term storage. From these types of studies, the appropriate excipients can be used to preserve the specific polymorphic form desired. However, even when the drug in its crystalline form is studied extensively, there are cases when a previously unknown polymorph may be formed in solution and lead to precipitation (14). 

In general, if an API form has stability problems in the bulk form, it is best to solve these issues via salt and form selection studies designed to discover and identify more thermodynamically stable forms prior to any excipient compatibility evaluation. It is known that different polymorphic forms and hydrated/solvated forms can have dramatically different stability profiles (23-26). 

The crystal structure of the cocrystal formed by celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide) with nicotinamide has been solved from powder X-ray diffraction data [54], The dissolution and solubility of the cocrystal product were found to depend on the medium involved, and a number of the observed phenomena were shown to originate from differences in conversion of the cocrystal celecoxib polymorphic forms I and III. However, through the judicious use of choice excipients, a formulation was developed that took advantage of the crystalline conversion to be up to fourfold more bioavailable than the celecoxib Form-Ill marketed product. 

Following the ICH (International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use) definition, an impurity is every separate chemical particle present in the active substance and final pharmaceutical product that is not the active substance or excipient. This includes all optical isomers, products of degradation, and polymorphic forms. The physicochemical properties and biological activity of dmg impurities can be similar or different to those of the active substance. Therefore, they can influence the human body in the same way as the medicinal product or differently [7] and lead to an increase or decrease in dmg activity. 

The occurrence of multiple polymorphic forms of crystalline drugs and excipients is well known to pharmaceutical scientists, and the possible occurrence of polymorphic forms of amorphous pharmaceutical... 

Furthermore, the monograph gives a definition of the terms active substance and excipients it explains the policy of the Commission concerning polymorphic forms, active substances of special grade, processing of active substances with and without the addition of excipients, and the two sets of identification tests that may be contained in a monograph. 

D-mannitol is a common carbohydrate excipient used in pharmaceutical formulations, and is known to exist in three anhydrous polymorphic forms. ... 

Mannitol is an isomer of sorbitol. Like the latter, it has a negative heat of solution which makes it a useful excipient for chewable tablets and lozenges. It is less hygroscopic than sorbitol and has about one-tenth of the solubility in water. Similarly to sorbitol, several polymorphic forms are available which differ in their ability to form tablets. " However, unmodified mannitol cannot be used for direct compression because of poor flow and binding properties. Directly compressible forms are available in a range of particle sizes which are reported to produce excellent tablets. 

The effect of temperature change on the stability of solid dosage forms can be complicated for many possible reasons. The dmg or one of the excipients may, for example, melt or change its polymorphic form as temperature is increased, or it may contain loosely bound water which is lost at higher temperatures. We should also remember that the relative humidity will change with temperature and so we must take care to keep this at a constant value. 

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