Tackling quantitative polymorphic analysis through fixed-dose combination tablets production. Pyrazinamide polymorphic assessment.

ANTONIO, MARINA; RAFFAGHELLI, MARIANO; MAGGIO, RUBÉN M.

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2020

0731-7085

Pyrazinamide (PZA), Rifampicin (RIF), Isoniazid (ISH) and Ethambutol (ETB) form thecore for the treatment of Tuberculosis, today a devastating disease in low-incomepopulations around the world. These drugs are usually administrated by fixed-dosecombination (FDC) products, to favour the patient compliance and prevent bacterialresistance.PZA exists in four enantiotropically-related polymorphs (Forms α, δ, β and γ), but onlyForm α is considered suitable for pharmaceutical products due to its stability andbioavailability properties. The classical approaches to address solid-state (microscopy,X-ray diffraction and calorimetry) shows limitations for quantification of polymorphs inthe presence of excipients and other active components, as in the case of FDC tablets.In this work, an overall strategy was developed using near infrared spectroscopy (NIR)coupled to partial least squares regression (PLS) to quantify Form α of PZA in drugsubstance (raw material) and PZA/RIF/ISH-FDC tablets. For this purpose, two PLSmodels were constructed, one for drug substance preparing training (n=30) andvalidation (n=18) samples with a ternary composition (Form α/Form δ/Form γ), andother for FDC drug products, also including the appropriate amount of RIF, ISH and thematrix of excipients in order to simulate the environment of PZA/RIF/ISH association.The NIR-PLS models were optimized using a novel smart approach based on radialoptimization (full range, 3 LV and MSC-D? and SNV-D? as pre-treatment, for rawmaterial and FDC tablets, respectively).During the validation step, both methods showed no bias or systematic errors andyielded satisfactory recoveries (102.5 ± 3.1% for drug substance and 98.7 ± 1.5% forFDC tablets).When commercial drug substance was tested, NIR-PLS was able topredict the content of Form α (0.98 ± 0.01 w/w). The model for FDC tablets allowedestimating polymorphic purity in intact (0.984 ± 0.003 w/w), sectioned (0.986 ± 0.002w/w), and powered (0.985 ± 0.004 w/w) tablets, showing the methodology could beapplied to a different stage of the process (i.e premixed-powders or granulates).Thesuitability of the method was also verified when Form α was satisfactorily analysed inFDC fortified with Form δ and Form γ to reach 0.78, 0.88 and 0.98 w/w, Form α. Thisstrategy results in an excellent alternative to ensure the polymorphic purity of PZAthroughout the overall pharmaceutical manufacturing process