Optimisation of preparation process of 0,2 mg hydrochlorothiazide capsules using a design of experiments

S Calland1, Y Bouattour1, L Szkudlara1, M Wasiak1, M Jouannet1, V Sautou1,2
(1) CHU Clermont-Ferrand, Pôle Pharmacie, F-63003 Clermont-Ferrand, France
(2) Université Clermont Auvergne, Institut de Chimie de Clermont- Ferrand. UMR CNRS 6296, F-63000 Clermont-Ferrand, France

Introduction
A review of preparations made between 2017 and 2018 in our pharmacy production unit showed that 0,2 mg hydrochlorothiazide (HCTZ) capsules have the highest rate of non-compliance (11 out of 19 noncompliant batches). All non-compliances were due to lack of content uniformity. A study was conducted to optimise the preparation process of these capsules.

Materials and Methods
A design of experiments (DOE), following a full factorial design, was made. DOE parameters and their levels were determined by observing 8 pharmacy technicians during capsules preparation. We prepared for each possible combination of parameters 3 batches of 100 capsules of 0,2 mg HCTZ. The output responses were acceptance value (AV) described by 2.9.40 monograph of the European Pharmacopeia, and batch reproductibility (BR) determined by intra and inter-day batch variances. The effect of each factor on these 2 responses was calculated. Then, the new process was tested with 9 batches made by 3 operators on different days. HCTZ quantitation were performed using valid UV spectrophotometry method. Compliance rates of prepared batches using the new process were compared to those made between 2017 and 2018, according to 2.9.6 and 2.9.40 monographs.

Results
Three factors were selected for the DOE: mixing time, location of powder during filling, adding order of ingredients into the mortar. 2 levels were determined for each parameters. 24 batches of 0,2 mg HCTZ capsules were realized. The effect calculation showed that AV decreases by 26,2%, and the BR is improved by 14,4% when mixing time extended from 2 to 8 minutes. The optimised process determined by the DOE was: 8 minutes of mixing, powder placed out of the capsule filling device, and alternating the adding order of ingredients into the mortar. The analysis of the 9 batches showed 100% compliance using the new process versus 42% for batches made in 2017/2018 according to 2.9.6 monograph. According to 2.9.40 monograph, 33% of the new batches were compliant versus 10% in 2017/2018 batches.

Discussion
Mixing time appears as the most influential factor on AV and BR. The compliance rate of the batches seems to be better with the new process. However, it still remains low according to 2.9.40 monograph.
Other factors could be investigated to improve compliance such as the use of other excipients or changing the size of capsules.

Conclusion
This new process enabled to get better results for capsules conformity. It will be applied during capsule preparation in our production unit. Further studies should be carried out to improve capsules conformity.

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