(M1030-07-38) Evaluation of In-Use and Accelerated Stability Studies of Platelet Aggregation Inhibitors: Clopidogrel Hydrogen Sulfate

Purpose: Clopidogrel hydrogen sulfate (CHS) is a widely used drug for the treatment of ischemic strokes, myocardial infarction, and vascular disease. It is an inhibitor of platelet activation and aggregation, achieved through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. It is reported that the effect of CHS varies among patients, being no responders or low responders. CHS belongs to BCS Class-II APIs with low solubility, limiting its oral bioavailability and therapeutic effectiveness. Commercial products use different salt forms of CHS in their dosage form. Typically, the desired solid state for a drug substance (API) is crystalline. Amorphous content within the crystalline drug substance may have a harmful impact on the drug product, such as reduced chemical and physical stability. Drug products, especially those dispensed in multi-dose containers or bulk pharmacy packaging, must maintain their integrity and quality during actual patient use (in-use) to achieve expected treatment outcomes. If a drug is susceptible to oxidation, constantly opening and closing the container during use may affect the quality of the product and cause differences in Treatment benefits. Other factors, such as temperature, light, and humidity, can impact the product throughout treatment. Therefore, understanding the stability of a drug product under both controlled and in-use conditions is crucial to ensure the drug molecule's integrity at the time of use.

Methods: The stability study was conducted on Four commercial 75 mg strength Clopidogrel hydrogen sulfate products (A, B, C, and D) kept in pharmacy vials at 30°C/75%RH, 25°C/60% RH, and HDPE  bottles at 40°C/75% RH  for 12 weeks. All the tablets' physical and chemical parameters were evaluated at 0, 4,8, and 12 weeks. At every time, the tablets were pulled out and analyzed using spectroscopic techniques such as Near-Infrared Spectroscopy (NIR), Fourier-transformed infrared spectroscopy (FTIR), and NIR hyperspectral images. Surface morphology was analyzed using scanning electron microscopy. Crystallinity was analyzed using the X-ray Powder Diffraction. Physical parameters were analyzed with the help of Hardness and Disintegration Time. Tablets were also analyzed for their dissolution and content (assay) using the compendia method, and the HPLC method was developed and validated. The amount of degradation impurity, i.e., impurity C, is also monitored at the above-mentioned time points with another HPLC-validated method.

Results: Near-Infrared Spectroscopy (NIR): The drug showed characteristic peaks in the region ∼4000–6000 cm^-1 due to CH, O-H, and N-H stretching vibrations of functional groups in the molecule. Fourier-transformed infrared spectroscopy (FTIR): CLP occurs in two forms, i.e., Form I and Form II. The FTIR spectrum of CLP can be divided into two regions – Finger print region (∼600-1900 cm^-1) and the high-frequency region (∼2000-3500 cm^-1). X-ray Powder Diffraction: The products ‘A’ and ‘D’ contain form II of CHS, and ‘B’ and ‘C’ contain form I of CHS peaks, which were observed. In all the products, an observed increase in the relative intensities of the peaks was observed. This change in intensity was attributed to the transformation from the amorphous form to the crystalline form during storage. Notably, the intensity consistently increased for all products at 30°C/75% RH and 40°C/75% RH over the entire 12-week weeks. Chemical Imaging: The surface of a pharmaceutical tablet is imaged by chemical imaging, and the distribution of the contained ingredients is visualized. The distribution and mixing uniformity of the active ingredient and excipients in the tablet were observed at all time points. Hardness and Disintegration Time: The tablet hardness and disintegration for all products at 30°C/75% RH for 12 weeks was observed to be consistent, but the products stored at 40°C/75% RH and 25°C/65% for 12 weeks were found to be increased. The hardness of all the evaluated products was found to increase with time. Dissolution: A consistent reduction in dissolution was observed at each time point compared to the initial dissolution rate. Specifically, products A, B, and C failed to meet the USP monograph limit after 12 weeks under intermediate storage conditions. Furthermore, in the long term, none of the formulations met the USP limit within the 12-week timeframe.

Conclusion: Clopidogrel is a Class II drug in the Biopharmaceutics Classification System. Despite its high permeability, it is characterized by its poor solubility in water. Various crystalline forms of clopidogrel exist. Our investigation revealed phase transformations in these crystalline forms, leading to increased crystallinity. This transformation, supported by Powder X-ray Diffraction data, resulted in slower solubility and dissolution rates of the drug over the past two weeks.