Pediatric syrups : impact of the API row material on the final preparation volume

Background
To compensate the lack of pediatric commercial formulations of many active pharmaceutical ingredients (API), our hospital pharmacy produces yearly several compounded magistral pediatric syrups (n=700 in 2019). Currently, the production method in based the volumetric Quantum Satis (QS) method: Diluent is added on API powder in a measuring cylinder and its volume is assessed at each production to reach a final volume. A short retrospective traceability data analysis showed possible variabilities of diluent volumes used for a same final product. These are dependent on operators, API powder compaction, environment factors (temperature, humidity…). A variable dilution volume means a variable endpoint API concentration. However, in order to optimize our resources and reduce the number of productions, we intend to produce these preparations with anticipated larger quantities. Called “Hospital Preparations”, these products are submitted according to the French regulations to qualitative and quantitative quality controls (QC), including API concentration assay. To define target concentration of the final product, our production process may need to be readapted and revalidated based on rigorously weighed ingredients.

Objectives
To assess the impact of API weighing method on the variability of final volumes and if needed, standardizes and validate the weighing preparation process by including the potential impact of the API volumetric characteristics.

Materiel and Methods
RM powder is weighed on a Mettler Toledo precision scale and is stirred into a small dlient volume volume (Syrspend®, Fagron, France). Then, the final volume is measured in a 100 mL measuring cylinder. Finally, the measure of the final volume is compared to the volume of the weighed syrup so as to assess the volume shift factor. The study was carried out with 12 API : ursodesoxycholic acid 30mg/mL (URS), amiodarone 1mg/mL (AD), amlodipine 1mg/mL (AM), baclofen 10mg/mL (BCL), hydrocortisone 1mg/mL (HC), isoniazid 10mg/mL (INH), melatonin 1mg/mL (MEL), propranolol 1mg/mL (PRO), spironolactone 2. 5mg/mL (SPR), sulfadiazine 100mg/mL (SD), thiamin 100mg/mL (THI) and topiramate 5mg/mL (TOP). 3 technicians were involved in the experiments, preparing each one 3 samples 60 mL for each formulation (one/day, 3 days). The data regarding API and syrups weighing and volumes were graphed in the BPPREP software. They allowed to assess the volume shift factors by means of accuracy and repeatability (CV) % : [m ± CV], compliant if < 5%.

Results
108 preparations were producedune . The RM displacement factors of the diluent are as follows: URS : 6.01 ± 1.6], AD : [-0.2 ± 0.32], AM : [-1.11 ± 0], BCL: [-0.54 ± 0.16], HC: [-1 ± 0.48], INH: [-0.59 ± 0.32], MEL: [-1.2 ± 0.32], PRO : [-1.35 ± 0.16], SPR : -1.61 ± 0.16], SD : [2.61 ± 0.78], THI : [4.75 ± 0.46], TOP : [-1.35 ± 0.65].

Discussion-Conclusion
Among the 12 molecules studied, 11 did not lead to major changes in the final volume with non-significant shift factors and no predictable impact on the final QC. Only the URS has a significant shift factor leading to an expansion of the diluent beyond 5 %, with a large bias. For URS, a specific production weighing process should be specifically set up, and margins of acceptation of QC results including the variability of the volume of RM from a preparation to another.

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