Tomasz Gnatowski, Remigiusz Bernaciak, Andrzej Marek Winnicki

Optimization of the preparation of metronidazole suspension suppositories by the pouring method in extemporaneous compounding, considering the influence of technological parameters on uniformity of mass and content uniformity

2026-01-30

Subject of Study. The preparation of suspension suppositories in pharmaceutical compounding constitutes one of the most significant technological challenges. A key issue in this process is the risk of sedimentation of the insoluble active ingredient within the molten base. Uncontrolled particle sedimentation leads to an uneven distribution of the drug across individual dosage units within a batch, resulting in a product with variable dosing. In the case of potent drugs or those with a narrow therapeutic index, this lack of homogeneity poses a direct threat to the safety of pharmacotherapy, creating a risk of administering subtherapeutic or toxic doses. Despite being extensively discussed in professional Western European literature, this issue has not yet been widely addressed in Polish literature.

Objective of the Study. The main objective of the study was a multifaceted evaluation of the influence of selected technological parameters and preparation techniques on the quality of metronidazole suppositories prepared by the fusion method using a cocoa butter base. The study aimed to identify the causes of dosage variation and to develop an optimized preparation protocol that would guarantee compliance with rigorous pharmacopoeial requirements regarding uniformity of mass and content in pharmacy practice settings.

Materials and Methods. The study involved a comparative analysis of eleven suppository preparation methods, differing in five parameters: degree of active substance comminution (very finely powdered – ≤ 125 µm vs. uncomminuted), pouring temperature of the suppository mass (28°C vs. 34°C), size of technological excess (none, 10% percentage excess, quantitative excess corresponding to the mass of 2, 3, or 5 suppositories), pouring technique (successive filling of mold cavities to the brim vs. topping-up technique), and stirring procedure during pouring (no stirring vs. stirring every third suppository). The variant with uncomminuted substance was included for comparative purposes to experimentally verify the scale of dose inhomogeneity resulting from a potential compounding error consisting of failure to perform the powdering process. Three independent batches of 12 suppositories were prepared for each method. The quality of the final product was verified through visual assessment, uniformity of mass testing, and metronidazole content determination. The key assessment criterion was the uniformity of dosage units, expressed as the Acceptance Value (AV), for which the pharmacopoeial batch acceptance criterion of AV ≤ 15.0 was adopted.

Results. The conducted analyses revealed drastic differences in suppository quality depending on the applied technology. Methods based on a percentage excess (10%) proved unsuitable for small batches (n = 12), leading to metronidazole content in the last poured suppositories exceeding 139–159% of the declared dose, which resulted in a high AV (26.4–42.8). Similar irregularities were observed for the two-stage topping-up technique, which generated suppositories with reduced mass and structural defects. Increasing the pouring temperature to 34°C resulted in suppository cracking and an AV > 22, while the lack of active substance comminution led to an AV ≈ 59.3. It was identified that the application of a quantitative excess (mass of 2–5 suppositories) is the key mechanism ensuring uniformity. Suppositories characterized by the lowest acceptance value (AV < 5.0) and precise mass were obtained exclusively with the simultaneous application of: comminution (≤ 125 µm), a pouring temperature of 28°C, stirring every third suppository, and a quantitative excess of 3–5 suppositories.

Conclusions. Obtaining suspension suppositories of quality compliant with the requirements of the Polish Pharmacopoeia XIII necessitates strict standardization of the compounding process. It was demonstrated that a percentage excess (10%) is inadequate for small suppository batches and must be replaced by a quantitative excess (minimum mass of 2 suppositories, optimally 3–5), which effectively eliminates the impact of sedimentation on the final dosage units. It is also mandatory to use suspended substances of appropriate particle size and to conduct the pouring process at 28°C with regular stirring.

Keywords: suppositories, metronidazole, compounded drug, quality control, pharmaceutical technology.

© Farm Pol, 2025, 81(7): 391–404