Ranitidine polymorphic forms

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. 

Bulk drug products often exist in different crystalline or polymorphic forms. Because the polymorphs of a specific API can exhibit dis-tinguishably different bulk stability properties as well as bioavailability characteristics as a result of the differences in surface area between the different crystalline forms, specification of the polymorphic form is recommended for FDA submission. Products such as ranitidine (10), lorazepam (11), and natamy-cin (12) serve as examples of APIs that exist in several different polymorphic forms. The solvent system and the crystallization conditions generally determine the specific crystallization form that is isolated. Polymorph selection for regulatory submission is usually based on the ability to reliably produce and process the material in the same crystalline form. In many cases this is the thermodynamically most stable polymorphic form. In the event that a less stable polymorphic form is desired, because of stability or bioavailability issues, seeding techniques can be used to control the crystallization selectivity of a specific polymorph. 

Crystallization remains the primary means of controlling the polymorphic or solva-tomorphic state of a compound, and various groups have examined the influences of processing parameters on the identity and quality of the isolated form. Seeding was used to reduce the size of the metastable zone of eflucimibe, and thereby control the identity of the desired polymorphic identity of the product through a reduction in concomitant crystallization [16], Process improvements have been developed that were found to improve the filterability and enhance the bulk density of ranitidine Form-1 [17], while the variation of process parameters used in an oscillatory baffled crystallizer enabled better selection to be made between the metastable a- and /i-forms of (z.)-glutamic acid [18]. 

Secondary processing does not always lead to phase transformations, as was shown during studies of the polymorphs of ranitidine hydrochloride [92]. No solid-solid transformation could be detected during either the grinding or compression of metastable Form I, stable Form II, or of a 1 1 mixture of these forms. The dissolution rates of both forms were found to be equivalent, and the solution-mediated transformation of Form I to Form II was observed to be slow. 

Fig.4.28 (a, b)IR spectra of (a) Form 1 and (b) Form 2 of ranitidine hydrochloride. The spectra are very similar (though not identical) in many respects, with one particularly distinguishing band at 1045 cm in the spectrum of Form 2. (From Cholerton et al. 1984, with permission.) Detail of the (c) Form 1 and (d) Form 2 FTIR spectra of the two polymorphs of ranitidine hydrochloride, including the instrument-determined location of individual peaks. (FromForster et al. 1998, with permission.)... 

When the FTIR spectra of polymorph systems differ substantially, the results may readily permit the identification of a particular form. For instance, the two forms of ranitidine hydrochloride yielded spectra that differed in the region above 3000 cm and in the regions spanning 2300-2700 cm and 1570-1620 cm b Zanoterone has been found to crystallize in a number of different forms, each of which yields a characteristic infrared spectrum. When solvent molecules are incorporated in a crystal lattice, the new structure is often sufficiently different from that of the anhydrous phase so that many of the molecular vibrational modes are altered. 

In a system having attained great notoriety owing to patent litigations, excellent sensitivity has been obtained in the use of quantitative XRPD for the quantitation of the polymorphs of ranitidine.25 Owing to significant nonoverlap, diffraction peaks suitable for the determination of either Form-I in bulk Form-II, or for Form-II in bulk Form-I, are easily identified. 

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