Blending Efficacy of PROSOLV® SMCC with Caffeine by Near-Infrared Spectroscopy

Abstract

In drug production, manufacturing effciency and the effectiveness of the final product (i.e., bioavailability, content uniformity, compression uniformity, ease of ejection, etc.) largely depends on the blending process. Not only do the chosen excipients used in the formulation matter, but any modification of these materials can contribute to major differences in the length of blending needed as well as the functionality of the blend, itself.

PROSOLV® SMCC (Co-processed Silicifed Microcrystalline Cellulose) was developed by JRS Pharma over 20 years ago. This monographed, Inactive Ingredient Database (IID) listed, highly functional excipient has been well regarded in formulation and processing. PROSOLV® SMCC improves compactability, exhibits superior flow, and enhances mixing characteristics, optimizing content uniformity thus enabling rapid formulation development. Direct compression processing remains the most economical process within pharmaceutical manufacturing due to a smaller processing equipment footprint with less steps and lower energy costs.

In this study, a series of blending experiments evaluated the uniformity of caffeine in blends with the co-processed excipient silicified microcrystalline cellulose (PROSOLV® SMCC) versus physical blends of microcrystalline cellulose and the glidant colloidal silicon dioxide (CSD). The blending process was monitored with Near-Infrared Spectroscopy (NIRS). The effects of mixing on particle size attenuation were investigated by measuring each of the resultant blends with a LASER light-scattering (LLS) device. The blends were tableted and the results (ejection force, hardness, and assay) compared.

For this un-optimized formulation with a challenging active, use of co-processed PROSOLV® SMCC yielded robust formulations with significant benefits over using MCC blended with CSD glidant. These benefits included faster blend uniformity and improved tablet content uniformity, as well as both increased tablet hardness and reduced ejection forces. PROSOLV® SMCC can be used to simplify formulation optimization and process scale-up, potentially avoiding costly reworks later on.

Aim of the Study

The goal of this study was to use NIRS to compare the blending efficacy of PROSOLV® SMCC with a physical blend of the samenominal components, using a challenging API in a nonoptimized model.

The blending e-cacy of PROSOLV® SMCC has been demonstrated visually, using pigments as a surrogate for the API in the formulation. NIRS was chosen for this study to allow measurement of blending efficacy with an API. There have been a large number of publications where NIRS has been used to determine the efficacy of mixing at any particular time point (ref. 1-5), though the focus has historically been on NIRS usability, relevant math treatments, or apparatus design. Caffeine was used as the model API since it is needle-like and has a high static charge, thus presenting challenges to insuring content uniformity.

Two blenders were used, one with a more vigorous motion, and another similar to plant-scale blenders, in order to observe the effects of both changing the excipients and the type of blender.

Formulation

PROSOLV® SMCC 90 and EMCOCEL® 90 M were chosen for the blending study because these materials have similar particle sizes and are both direct compression (DC) excipient grades. The commercial lots of PROSOLV® SMCC 90 and EMCOCEL® 90 M (JRS Pharma) used had similar bulk densities (0.36 g/mL and 0.33 g/mL, respectively) to reduce density effects on blending. The CSD used for the EMCOCEL® -CSD blend was the same grade as is used in PROSOLV® SMCC. Two formulations were made targeting the same final composition of API (caffeine, 10%) and the same nominal composition of excipients (see Table 1). There was no formulation optimization. Sodium starch glycolate (SSG, EXPLOTAB®) was incorporated into the blend first, then the CSD (Cab-O-Sil® M-5P), before the caffeine was finally added. Caffeine (USP) was obtained from Spectrum Chemical. Sodium stearyl fumarate (SSF, PRUV®) was screened and added to each blend after NIRS measurements were complete, with an additional five minutes of blending time.

Tab. 1 Target compositions (%w/w).

Excipients

PROSOLV® SMCC (silicified microcrystalline cellulose – SMCC), is a unique combination of MCC co-processed with colloidal silicon dioxide. A high functionality and multifunctional excipient, it facilitates less complex processing, has higher inherent functionality, and passes that functionality on to the drug formulation. It nominally contains 98 % MCC and 2.0 % CSD.

EMCOCEL® Microcrystalline Cellulose (MCC) is one of the most widely used binder excipients in tablet formulations. Derived from pharmaceutical grade wood pulp, it offers a wide range of chemical, technical, and economical benefits in formulation and processing.

PRUV® (Sodium Stearyl Fumarate) is a tablet lubricant that offers a high degree of API compatibility and robustness to over-lubrication.

EXPLOTAB® (Sodium Starch Glycolate) is a swelling-type superdisintegrant for tablets and other oral solid dosage forms.

Cab-O-Sil M-5P (Colloidal Silicon Dioxide) is used as a flow aid in the tableting process.

Procedure

Equipment

Blending

Each blend was prepared twice, once with a batch size of 330 g (for a 2L Glen Mills Turbula), and again with a batch size of 660 g (for a 4 qt PK V-blender), in both cases targeting between one third to half of the fill volume. The Turbula was run at 72 rpm, and the V-blender at 25 rpm. Five samples were taken at pre-chosen intervals, each transferred into a 25 mL sample vial, and NIR spectra were obtained. In consideration of sampling and its potential impact to the blend, the thieved samples were returned to the blender prior to the next mix point.

NIRS Measurements

In order to follow the variance in the homogeneity of the ingredients in the mixes, caffeine was selected as the “spectroscopic marker” for the analyses. A caffeine peak at 1670 nm was chosen as the analytical marker, as it is easily identified in the spectrum (Figure 1).

Five samples (taken from various locations/depths at each time point) by the “sample thief,” were transferred to glass vials and scanned (reflection mode through the bottom of the vial) via NIRS. The diffuse reflection spectra were obtained in triplicate for each sample, with reproducible shaking and tapping between measurements.

Fig. 1 NIR of blend study materials – caffeine peak at 1670 nm.

Tableting

After addition of the lubricant at the end of each blending experiment, each blend was compacted into tablets. Best practice is for samples to be no more than 3x a unit dosage. As the sampling thief could remove up to three grams of sample for NIR measurements, a final target weight of 1500 mg was chosen. A 0.875” (22.2 mm) round flat faced beveled edge tooling was used to accommodate the large tablet size. Each blend was compacted at five different compaction forces, on an instrumented tablet press.

Conclusion

PROSOLV® SMCC produced blends with better uniformity (as easured by NIRS) than the EMCOCEL® -CSD blends. Use of PROSOLV® SMCC promoted faster blend uniformity with a challenging active, allowing shorter processing times. Blends with PROSOLV® SMCC demonstrated increased tablet hardness and reduced ejection forces as compared to those with EMCOCEL® -CSD. Caffeine assay results, particularly the acceptance value, pointed to the PROSOLV® SMCC Turbula blend as producing the best overall blend, improving both content uniformity and content accuracy of the resulting tablets.

For this un-optimized formulation with a challenging API, use of the co-processed PROSOLV® SMCC excipient yielded robust formulations with significant benefits over using MCC blended with CSD glidant. These benefits included faster blend uniformity and improved tablet content uniformity, as well as both increased tablet hardness and reduced ejection forces. PROSOLV® SMCC can be used to simplify formulation optimization and process scale-up.

See the full technical brochure on “Blending Efficacy of PROSOLV® SMCC” here

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Source: JRS Pharma, technical brochure Blending Efficacy of PROSOLV® SMCC, website www.jrspharma.com, https://www.jrspharma.com/pharma_en/media-library/data/prosolv-smcc-with-caffeine.php

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