Magistral preparation of chloroquine phosphate capsules for the treatment of lupus patients: Example of an active principle with a narrow therapeutic range requiring manipulation under conditions

Introduction et Objective
Hydroxychloroquine (HCQ) is the only initial pharmacological option for the chronic treatment of lupus. However, in rare cases, HCQ is responsible for significant cutaneous hyperpigmentation. In this study, we assessed the feasibility of a magistral preparation of chloroquine phosphate (PCQ), taking into account production constraints and the narrow therapeutic range of PCQ.

Materials and Methods
The formulation of PCQ immediate-release capsules (size 3) (Class I active substance in the biopharmaceutical classification system; 160 mg equivalent to 100 mg chloroquine base) was inspired by the Chloroquine Phosphate Tablets, USP monography (i.e, 30 mg microcrystalline cellulose, CMC, filling excipient) PCQ capsules were prepared in a semi-automatic capsule filler located in a glove box by pharmacy technicians wearing personal protective equipment (FFP3 mask, gown, overblouse, overshoe, gloves) due to the toxicity of the active ingredient (reprotoxicity and organ toxicity). The homogeneity of the PCQ powder mixture was assessed macroscopically by observing the fluorescence of the mixture under a UV lamp (254 and 312 nm). A UV spectrophotometric assay for PCQ in the PCQ/CMC mixture was developed to perform an uniformity of content assay after dissolving and then diluting the contents of 10 capsules in reverse osmose-purified water. Uniformity of mass was determined by weighing 20 capsules. A Fourier transformed infrared spectrum of the PCQ/CMC mixture has been obtained.

Results
To produce 100 capsules (size 3) of PCQ 160 mg, 16 g of PCQ and 3 g of CMC were mixed for 10 minutes in an automatic mixer. Capsules were stored in a desiccant-lidded container. Spectrophotometric determination of PCQ in the mixture showed a linear relationship between absorbance and concentration at a wavelength of 343 nm (R = 0.997), and a maximum coefficient of variation of 2.73%. Mass and content uniformity were in line with European Pharmacopoeia specifications, with a maximum deviation from the mean of 9.26% and 4.21%, respectively.

Discussions and conclusions
This study demonstrates the feasibility of preparing PCQ capsules for the treatment of lupus patients, in response to cutaneous intolerance to HCQ. Despite the difficulties of handling PCQ, our preparation method was rigorously developed and validated. Results confirmed the homogeneity of the PCQ/CMC mixture by infrared spectroscopy and observation under UV lamp. In addition, spectrophotometric assays demonstrated a reliable linear relationship for quantifying PCQ in capsules. This approach meets clinical requirements for effective lupus management, guaranteeing the quality and efficacy of customized PCQ formulations tailored to specific patient needs.

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