Application of Response Surface Methodology to Estimate the Design Space of Pharmaceutical Diluents for Dispensing Powdered Formulations

Abstract

Scientific approaches for dispensation are important for the quality and efficacy of drug treatments. Therefore, for the dispensation of powdered medicines, we have developed a powder blending method using a planetary centrifugal mixer (PCM) to replace the empirical manual method involving a mortar and pestle. The aim of this study was to optimize the formulation of pharmaceutical diluents for dispensing powdered medicines, using PCM. The diluents, composed of powdered lactose, crystalline lactose, and corn starch were assigned to a {3,2}-Simplex Lattice design. Then, the designed diluents were blended with model powders, such as carbazochrome sodium sulfonate powder, rifampicin capsule contents, and crushed sulfasarazine tablets, at ratios of 1 : 4, 1 : 1, and 4 : 1 using PCM at 800 rpm for 60 s at a 20% filling rate. The mixtures were examined for content uniformity relative standard deviation (RSD) and flowability angle of repose (AOR). Response surface methodology was applied to optimize the formulation with the smallest RSD and AOR, and then the design space of desired diluents was estimated. On the basis of the design space, crystalline lactose, the mixture of lactose powder and crystalline lactose at a ratio of 1 : 4, and the mixture of corn starch and crystalline lactose at a ratio of 1 : 4, were suitable diluents for the powdered formulation, the content of the capsules, and the crushed tablets, respectively. The selected diluents were successfully applied to other model medicines showing a sufficient RSD and AOR. This technique could contribute to the development of scientific approaches for dispensation.Key words pharmaceutical diluent; planetary centrifugal mixer; design space; response surface methodology; content uniformityTo ensure the quality of drugs and efficacy of drug treatments, scientific methods must shift from the manual empirical method to a mechanical one even in the case of extemporaneous dispensation. It has been reported that powdered drugs dispensed according to the same recipe showed different efficacies depending on the pharmacist who dispensed the drugs.1) This limitation is the result of dispensing procedures, including powder blending. Therefore, we have proposed a powder blending method using a planetary centrifugal mixer (PCM) instead of the manual method involving a mortar and pestle.2) Recently, Saito et al. reported that PCM was the most appropriate method for the preparation of low-dose tacrolimus because of efficiency and consistent quality.3) PCM is a container mixer without any agitators.4) The closed container rotates while it revolves in the mixer, resulting in more powerful mixing. PCM was well established as an ointment mixer, and was introduced to many pharmacies. Furthermore, Miyazaki et al. have applied PCM to dry-powder coatings with fine particles.5) With PCM, the degree of blending is not influenced by operators who have different technical abilities. In addition, cross-contamination is avoided when a disposable counter is used. 6)Powdered medicines are frequ...

Extemporaneous preparation of rifampicin granules from capsules to improve usability

“…In a few cases, tablets and capsules are reformulated into powder formulations to regulate the dose of the medicines. 4 However, weight loss of the powders during dispensing and administration due to their bulky and adhesive properties creates challenges. Therefore, we considered that, for children or elderly patients, the granule form would be more preferable.…”

Small-Scale Spherical Granulation Using a Planetary Centrifugal Mixer

“…4) Although the PCM has many advantages over other mixing machines for blending materials, it has only been used for kneading ointments in clinical settings. 5,6) Recently, we reported the feasibility of using a PCM for producing uniform powder blends [7][8][9] free from cross-contamination due to use of disposable vessels. 10) However, use of a PCM for small-scale spherical granulation has not been previously reported.…”