Purpose: Polymorphism is the ability for a solid to exist as two or more crystalline phases that have different arrangements of molecules in the crystal lattice. Polymorphisms can have profound effects on the physical and chemical properties of drug substances and drug products, which can result in changes in solubility, dissolution, stability, bioavailability, and hence, efficacy of a drug. Therefore, characterization of polymorphs is necessary in the pharmaceutical drug development process to determine a drug’s pharmacokinetic and pharmacodynamic properties. Ranitidine Hydrochloride (RHCl), BCS class III, is a histamine-2 blocker that exists in two polymorphic forms, Form I and II. Various analytical techniques (SEM, FTIR, Raman, PXRD, DSC) were used to characterize the polymorphic forms of the API, as well as the brand and generic OTC drug products, Zantac® and Equate, respectively. The use of these techniques is critical in monitoring polymorphic transformations due to pharmaceutical processes, such as milling, compression, stability and storage conditions.
Methods: A Zeiss-1450EP SEM was used on RHCl Forms I and II to show a difference in particle morphology based on crystallinity. A Bruker Alpha FT-IR was used compare the absorption bands and a Bruker BRAVO Raman was used to analyze the Raman shifts of the drug substance and drug product. Powder X-Ray Diffraction (PXRD) patterns were obtained using a Bruker D8 XRD. PXRD was used to illustrate that the difference in crystalline structure of the drug substances and drug products by examining angular position, relative intensities, and diffraction line profiles of the diffraction patterns. DSC thermograms of the RHCl Forms I and II were obtained using a Perkin Elmer DSC 6000. DSC was used to show the difference in endothermic peaks and the heat of enthalpy of the drug substances based on their crystallinity.
Results: SEM for RHCl Forms I and II confirmed that the drug substances had different particle morphologies based on the polymorphic form. The FT-IR spectra showed slight shifts in peak wave numbers, intensities, and presence of new peaks due to different dipole moments, as a result of crystal structure differences of the polymorphs. FT-IR illustrated that the API in Zantac® is RHCl Form II, whereas the API in Equate is RHCl Form I. Raman spectroscopy also confirmed this by comparing the Raman shifts of the drug substance to the drug product. PXRD showed a clear difference between angular position and relative intensities of the diffraction patterns based on the crystallinity, allowing for identification and characterization of drug substances and products. DSC thermograms of the RHCl Forms I and II show a difference in endothermic phase transition and heat of enthalpy based on the crystallinity, confirming that DSC is capable of distinguishing between polymorphs. All of these analytical techniques were able to identify the two polymorphs in the drug substance and drug product. Different techniques can be chosen based on the availability of the solid substance. For example, PXRD and Raman are nondestructive analytical techniques and are preferred when small amounts of the API are available.
Conclusion: RHCl is a histamine-2 blocker that exists in two polymorphic forms, Form I and II. During pharmaceutical drug development, processing steps must be carefully selected and monitored to prevent polymorphic transformations. The results indicate that a combined use of these analytical techniques can successfully differentiate between polymorphic forms of a drug substance and drug product. Furthermore, these analytical techniques can be used to identify and confirm the crystalline nature of the drug substance used in the manufacture of the drug product. In addition, all of the analytical techniques used clearly differentiated the polymorphs in our drug substance and products. However, this might not always be the case depending on the drug substance. Therefore, a combination of these techniques can allow for successful differentiation and identification of polymorphs.
Gurvinder Singh Rekhi– Academic Faculty Associate, University of Georgia College of Pharmacy, Athens, Georgia