Development of nanodispersion-based sildenafil metered-dose inhalers stabilized by poloxamer 188: a potential candidate for the treatment of pulmonary arterial hypertension.

Objectives: This study aims to formulate nanodispersion-based sildenafil metered-dose inhalers (MDIs) by using poloxamer 188 (P188) as a stabilizer; to evaluate their stability, aerosol characteristics, cytotoxicity, and inflammatory effects; and to investigate the effects of P188 on stability and aerosol characteristics of the MDIs. Methods: The stability and uniformity of the formulations were evaluated by high-performance liquid chromatography method. The aerosol characteristics were evaluated by the Next Generation Impactor. The cytotoxicity and inflammatory effects on respiratory epithelial cells and alveolar macrophages were evaluated by MTT assay and TNF-α, IL-1ß, and NO assay, respectively. Results: The optimal formulation was stable and well-uniform after 6 months. The fine particle fraction and mass median aerodynamic diameter (MMAD) of the formulation were 61.9% ± 2.5% and 1.69 ± 0.06 µm, respectively. The formulation was found to be nontoxic to respiratory epithelial cells and did not induce the inflammatory responses of alveolar macrophages. A positive correlation between P188 concentration and MMAD of the MDIs was observed. P188 possesses an ability to prevent the growth of sildenafil citrate monohydrate crystals in the formulations. Conclusions: The findings provided a basis for the development of sildenafil MDI as a potential candidate for the treatment of pulmonary arterial hypertension.

Bulk Freeze-Drying Milling: a Versatile Method of Developing Highly Porous Cushioning Excipients for Compacted Multiple-Unit Pellet Systems (MUPS).

The compaction of multiple-unit pellet system (MUPS) is a challenging process due to the ease of coat damage under high compression pressure, thereby altering drug release rates. To overcome this, cushioning excipients are added to the tablet formulation. Excipients can be processed into pellets/granules and freeze-dried to increase their porosity and cushioning performance. However, successful formation of pellets/granules has specific requirements that limit formulation flexibility. In this study, a novel top-down approach that harnessed bulk freeze-drying milling was explored to avoid the challenges of pelletization/granulation. Aqueous dispersions containing 20%, w/w hydroxypropyl methylcellulose (HPMC), partially pregelatinised starch or polyvinylpyrrolidone alone, and with lactose (Lac) in 1:1 ratio, were freeze-dried and then milled to obtain particulate excipients for characterization and evaluation of their cushioning performance. This study demonstrated that bulk freeze-drying milling is a versatile method for developing excipients that are porous and directly compressible. The freeze-drying process modified the materials in a unique manner which could impart cushioning properties. Compared to unprocessed excipients, the freeze-dried products generally exhibited better cushioning effects. The drug release profile of drug-loaded pellets compacted with freeze-dried Lac-HPMC excipients was similar to that of the uncompacted drug-loaded pellets (f 2 value = 51.7), indicating excellent cushioning effects. It was proposed that the specific balance of brittle and plastic nature of the freeze-dried Lac-HPMC composite conferred greater protective effect to the drug-loaded pellets, making it advantageous as a cushioning excipient.

Preparation of co-spray dried cushioning agent containing stearic acid for protecting pellet coatings when compressed.

This study investigated the applicability of stearic acid as a co-adjuvant in cushioning agent formulated to prevent coat damage when compressing coated pellets. The co-processed and physical blended fillers were prepared by spray drying and physically blending, respectively, with filler ingredients consisting of stearic acid, microcrystalline cellulose, fully gelatinized starch, and corn starch. Pellets containing drug were produced by coating onto non-pariels a drug layer of metformin followed by a sustained-release layer. Drug release from tablets composed of co-processed or physical blended fillers (0, 1, 5, and 10% stearic acid levels) and coated drug containing pellets were analyzed using similarity factor F2. Under the same force and the stearic acid level, co-processed fillers produced pellet containing tablets which showed higher F2 or t50 values and tensile strengths as well as lower yield pressures as compared with tablets containing physical blended fillers. It was shown that the destructive degree of pellet coating was significantly reduced after being co-processed by homogenization and the incorporation of stearic acid in the cushioning agents, as shown by the improved F2 and t50 values. In addition, disintegrate times of tablets containing co-processed agents decreased despite the hydrophobic stearic acid. In conclusion, the inclusion of stearic acid in co-processed cushioning agents was effective at protecting compacted coated pellets from compression-induced damage without compromising disintegratability. The findings could serve as a step towards resolving the technical challenges of balancing the drug release profiles, tablet tensile strength, and disintegration time of compacting coated pellets into multi-particulate-sustained release tablets.

Impact of HPMC on the physical properties of spray-congealed PEG microparticles and its swelling effect on rifampicin dissolution.

CONTEXT: Many active substances are poorly water-soluble and pose a great challenge when orally administered because drug bioavailability is largely dependent on its solubility. OBJECTIVE: The objective of this investigation was to evaluate the effect of hydroxypropyl methylcellulose (HPMC) as an additive on the physical properties of spray-congealed polyethylene glycol (PEG) microparticles. MATERIALS AND METHODS: The effects of four viscosity grades of HPMC (K100 LV, K4M, K15M and K100M) on the spray-congealing process yield and physical properties of spray-congealed microparticles, such as morphology and particle size, were studied. The swelling effect of HPMC on drug release was also explored using surface plots. RESULTS AND DISCUSSION: Molten mixtures containing PEG and HPMC of various grades and concentrations were successfully spray-congealed with useful yield ranging from 42.6% to 58.4%. Smooth and spherical microparticles were produced and their size was found to increase with increasing feed viscosity. The swelling extent of microparticles was found to be influenced by the grade, particle size and amount of HPMC present while the rate of erosion depended on the formation of the barrier and grade of HPMC used. Formulations with appropriate rates of erosion were selected to prepare microparticles with rifampicin (RIF), a poorly water-soluble drug. At 10% (w/w), K100 LV was found to enhance the dissolution of RIF while K15M retarded the release. CONCLUSION: The novel application of HPMC as an additive in spray-congealed PEG microparticles not only affected the physical properties of the microparticles but also modified the drug release by its swelling effect.

A study on the impact of hydroxypropyl methylcellulose on the viscosity of PEG melt suspensions using surface plots and principal component analysis.

An understanding of the rheological behaviour of polymer melt suspensions is crucial in pharmaceutical manufacturing, especially when processed by spray congealing or melt extruding. However, a detailed comparison of the viscosities at each and every temperature and concentration between the various grades of adjuvants in the formulation will be tedious and time-consuming. Therefore, the statistical method, principal component analysis (PCA), was explored in this study. The composite formulations comprising polyethylene glycol (PEG) 3350 and hydroxypropyl methylcellulose (HPMC) of ten different grades (K100 LV, K4M, K15M, K100M, E15 LV, E50 LV, E4M, F50 LV, F4M and Methocel VLV) at various concentrations were prepared and their viscosities at different temperatures determined. Surface plots showed that concentration of HPMC had a greater effect on the viscosity compared to temperature. Particle size and size distribution of HPMC played an important role in the viscosity of melt suspensions. Smaller particles led to a greater viscosity than larger particles. PCA was used to evaluate formulations of different viscosities. The complex viscosity profiles of the various formulations containing HPMC were successfully classified into three clusters of low, moderate and high viscosity. Formulations within each group showed similar viscosities despite differences in grade or concentration of HPMC. Formulations in the low viscosity cluster were found to be sprayable. PCA was able to differentiate the complex viscosity profiles of different formulations containing HPMC in an efficient and time-saving manner and provided an excellent visualisation of the data.

Influence of Hydroxypropyl Methylcellulose on Metronidazole Crystallinity in Spray-Congealed Polyethylene Glycol Microparticles and Its Impact with Various Additives on Metronidazole Release.

The purpose of this study was to investigate the effect of a hydrophilic polymer, hydroxypropyl methylcellulose (HPMC), on the crystallinity and drug release of metronidazole (MNZ) in spray-congealed polyethylene glycol (PEG) microparticles and to further modify the drug release using other additives in the formulation. HPMC has been used in many pharmaceutical formulations and processes but to date, it has not been employed as an additive in spray congealing. Crystallinity of a drug is especially important to the development of pharmaceutical products as active pharmaceutical ingredients (APIs) are mostly crystalline in nature. A combination of X-ray diffractometry, differential scanning calorimetry, Raman spectroscopy and Fourier transform-infrared spectroscopy (FT-IR) spectroscopy was employed to investigate the degree of crystallinity and possible solid-state structure of MNZ in the microparticles. The microparticles with HPMC were generally spherical. Spray congealing decreased MNZ crystallinity, and the presence of HPMC reduced the drug crystallinity further. The reduction in MNZ crystallinity was dependent on the concentration of HPMC. Smaller HPMC particles also resulted in a greater percentage reduction in MNZ crystallinity. Appreciable modification to MNZ release could be obtained with HPMC. However, this was largely attributed to the role of HPMC in forming a diffusion barrier. Further modification of drug release from spray-congealed PEG-HPMC microparticles was achieved with the addition of 5% w/w dicalcium phosphate but not with magnesium stearate, methyl cellulose, polyvinylpyrrolidone, silicon dioxide and sodium oleate/citric acid. Dicalcium phosphate facilitated formation of the diffusion barrier.

Tableting of coated multiparticulates: Influences of punch face configurations.

The influences of the punch face design on multi-unit pellet system (MUPS) tablets were investigated. Drug-loaded pellets coated with sustained release polymer based on ethylcellulose or acrylic were compacted into MUPS tablets. Punch face designs used include standard concave, deep concave, flat-faced bevel edge and flat-faced radius edge. MUPS tablets compacted at 2 or 8 kN were characterized for their tensile strength. The extent of pellet coat damage after tableting was evaluated from drug release profiles. Biconvex tablets were weaker by 0.01-0.15 MPa, depending on the pellet type used, and had 1-17 % higher elastic recovery (p < 0.000) than flat-faced tablets. At higher compaction force, the use of the deep concave punch showed a 13-26 % lower extent of pellet coat damage, indicated by a relatively higher mean dissolution time, compared to other punch face configurations (p < 0.000). This was attributed to increased rearrangement energy of the compacted material due to the high punch concavity, which sequestered compaction stress exerted on pellet coats. Although the deep concave punch reduced the stress, the resultant tablets containing pellets coated with acrylic were weaker (p = 0.01). Overall, the punch face configuration significantly affected the quality of MUPS tablets.

Selection of lubricant type and concentration for orodispersible tablets.

Lubricants are essential for most tablet formulations as they assist powder flow, prevent adhesion to tableting tools and facilitate tablet ejection. Magnesium stearate (MgSt) is an effective lubricant but may compromise tablet strength and disintegratability. In the design of orodispersible tablets, tablet strength and disintegratability are critical attributes of the dosage form. Hence, this study aimed to conduct an in-depth comparative study of MgSt with alternative lubricants, namely sodium lauryl sulphate (SLS), stearic acid (SA) and hydrogenated castor oil (HCO), for their effects on the tableting process as well as tablet properties. Powder blends were prepared with lactose, sodium starch glycolate or crospovidone as the disintegrant, and a lubricant at different concentrations. Angle of repose was determined for the mixtures. Comparative evaluation was carried out based on the ejection force, tensile strength, liquid penetration and disintegratability of the tablets produced. As the lubricant concentration increased, powder flow and tablet ejection improved. The lubrication efficiency generally decreased as follows: MgSt > HCO > SA > SLS. Despite its superior lubrication efficacy, MgSt is the only lubricant of four evaluated that reduced tablet tensile strength. Tablet disintegration time was strongly determined by tensile strength and liquid penetration, which were in turn affected by the lubricant type and concentration. All the above factors should be taken into consideration when deciding the type and concentration of lubricant for an orodispersible tablet formulation.

Functionality of wet-granulated disintegrant in comparison to directly incorporated disintegrant in a poorly water-soluble tablet matrix.

Tablet disintegration is crucial for drug release and subsequent systemic absorption. Although factors affecting the disintegrant's functionality have been extensively studied, the impact of wet granulation on the performance of disintegrants in a poorly water-soluble matrix has received much less attention. In this study, the disintegrants, crospovidone (XPVP), croscarmellose sodium (CCS) and sodium starch glycolate (SSG), were wet-granulated with dibasic calcium phosphate dihydrate as the poorly water-soluble matrix and polyvinylpyrrolidone as the binder. The effect of wet granulation was studied by evaluating tablet tensile strength and disintegratability. Comparison between tablets with granulated or ungranulated disintegrants as well those without disintegrants were also made. Different formulations showed different degrees of sensitivity to changes in tablet tensile strength and disintegratability post-wet granulation. Tablet tensile strength decreased for tablets with granulated disintegrant XPVP or CCS, but to a smaller extent for SSG. While tablets with granulated XPVP or CCS had increased disintegration time, the increment was lesser than for SSG, suggesting that wet granulation impacted a swelling disintegrant more. The findings showed that tablets with wet-granulated disintegrant had altered the disintegrant's functionality. These findings could provide better insights into changes in the disintegrant's functionality after wet granulation.

Mannitol-coated hydroxypropyl methylcellulose as an alternative directly compressible controlled release excipient.

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC-mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC-mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC-mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150-200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC-mannitol ratios. Co-processed HPMC-mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression.

Elucidation of monomerization effect of PVP on chlorin e6 aggregates by spectroscopic, chemometric, thermodynamic and molecular simulation studies.

Molecular aggregation in aqueous media is one of the factors which largely affects the efficacy of photosensitizers in photodynamic therapy. Chlorin e6 (Ce6) in aggregated form is known to exhibit markedly reduced therapeutic effects. In the present study, aggregate to monomer conversion of Ce6 was investigated as a function of pH and polyvinylpyrrolidone (PVP) concentration by simple absorption and fluorescence spectroscopic techniques. Aggregation of Ce6 was observed in the pH range of 2 to 6 as indicated by changes in UV-vis absorption spectra, fluorescence emission spectra and relative quantum yield. Novel chemometric approach was considered for determining the relative monomerization efficiency of different grades of PVP. The chemometric analysis and binding constant study both strongly revealed that the Ce6-PVP complex was more efficiently formed with PVP of the lowest molecular weight (K17). Thermodynamic parameters, such as the heat of entropy and enthalpy, showed that complex formation was largely attributed to hydrophobic interaction between Ce6 and PVP. This was found to be consistent with the results obtained from molecular simulation study.

Insights into the functionality of pelletization aid in pelletization by extrusion-spheronization.

This study investigated the particle sizes of pelletization aids from the different wet processing steps of extrusion-spheronization, and their influence on rheological and pellet properties. Three commercial microcrystalline cellulose (MCC) grades, three commercial cross-linked polyvinyl pyrrolidone (X-PVP) grades and two agglomerated X-PVP grades (prepared using roller compaction from two commercial fine particle size X-PVP grades) were used as pelletization aid. The pelletization aids were analyzed for their dry state particle size, individual particle size (sonicated powder dispersion in water) and in-process particle sizes (dispersions of processed materials from the different processing steps). No remarkable particle size changes were observed with the commercial X-PVP grades under the different conditions. The two fine X-PVP grades, but not the coarse grade, produced good quality pellets. MCC and agglomerated X-PVP grades exhibited spectacularly lower individual and in-process particle sizes, and produced good quality pellets although some of them had dry state particle sizes comparable to that of the commercial coarse X-PVP grade. In-process particle sizes of pelletization aids correlated strongly with the rheological and pellet properties of the pelletization aid:lactose (1:3) binary mixtures. These results demonstrated that small in-process particle size of pelletization aid is a critical requirement for successful pelletization by extrusion-spheronization.

Alginate-based matrix tablets for drug delivery.

INTRODUCTION: As a nature-derived polymer with swelling and gelling properties, alginate has found wide biopharma-relevant applications. However, there is comparatively limited attention on alginate in tablet formulations. Therefore, this review aimed to provide an overview of the applications of alginate in solid dosage form formulations. AREAS COVERED: This review outlines the role of alginate for oral sustained release formulations. For better insights into its application in drug delivery, the mechanisms of drug release from alginate matrices are discussed alongside the alginate inherent properties and drug properties. Specifically, the influence of alginate properties and formulation components on the resultant alginate gel and subsequent drug release is reviewed. Modifications of the alginate to improve its properties in modulating drug release are also discussed. EXPERT OPINION: Alginate-based matrix tablets is useful for sustaining drug release. As a nature-derived polymer, batch consistency and stability raise some concerns about employing alginate in formulations. Furthermore, the alginate gel properties can be affected by formulation components, pH of the dissolution environment and the tablet matrix micro-environment pH. Conscientious efforts are pivotal to addressing these formulation challenges to increase the utilization of alginate in oral solid dosage forms.

Influence of talc and hydrogenated castor oil on the dissolution behavior of metformin-loaded pellets with acrylic-based sustained release coating.

Multi-unit pellet system (MUPS) is of great interest as it is amenable to customization. MUPS comprises multi-particulates, usually as pellets or spheroids, which can be coated with diffusion barrier coatings. One commonly used diffusion barrier coating is the methacrylic acid copolymer, which can be used as a taste masking, enteric or sustained release polymer. While the versatility of methacrylic acid copolymers makes them pliable for pellet coating, there are impediments associated with their use. Additives commonly required with this polymer, including plasticizer and anti-adherent, have been shown to weaken the film strength. The objective of this study was to investigate the impact of osmotic pressure within the core on the sustained release coat integrity and functionality. Hydrogenated castor oil (HCO) was chosen as the additive to be studied. Metformin-loaded pellets, prepared via extrusion-spheronization, were coated with ethyl acrylate and methyl methacrylate copolymer (Eudragit RS 30 D) containing talc, talc-HCO, or HCO to different coat thicknesses. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. The swelling of the pellets when wetted was monitored by video imaging through a microscope. When coated to 7.5 % coat weight gain, coats with HCO slowed down drug release more than the other pellets. The pellets also swelled the most, which suggests that they were more resistant to the osmotic pressure exerted by metformin. For drugs which exert high osmotic pressure, HCO can serve as an efficient alternative to talc in the preparation of methacrylic acid copolymer coatings.

Evaluation of the physicochemical properties and compaction behavior of melt granules produced in microwave-induced and conventional melt granulation in a single pot high shear processor.

Recently, microwave-induced melt granulation was shown to be a promising alternative to conventional melt granulation with improved process monitoring capabilities. This study aimed to compare the physicochemical and compaction properties of granules produced from microwave-induced and conventional melt granulation. Powder admixtures comprising equivalent proportions by weight of lactose 200 M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350 under the influence of microwave-induced and conventional heating in a 10-L single pot high shear processor. The properties of the granules and compacts produced from the two processes were compared. Relative to conventional melt granulation, the rates at which the irradiated powders heated up in microwave-induced melt granulation were lower. Agglomerate growth proceeded at a slower rate, and this necessitated longer massing durations for growth induction. These factors prompted greater evaporative moisture losses from the melt granules. Additionally, nonuniform heating of the powders under the influence of microwaves led to increased inter-batch variations in the binder contents of resultant melt granules and a reliance of content homogeneity on massing duration. Agglomerate growth proceeded more rapidly under the influence of conventional heating due to the enhanced heating capabilities of the powders. Melt granules produced using the conventional method possessed higher moisture contents and improved content homogeneity. The compaction behavior of melt granules were affected by their mean sizes, porosities, flow properties, binder, and moisture contents. The last two factors were responsible for the disparities in compaction behavior of melt granules produced from microwave-induced and conventional melt granulation.

Influence of the porosity of cushioning excipients on the compaction of coated multi-particulates.

The compaction of multiple unit-pellet system (MUPS) tablets poses considerable challenges due to potential compaction-induced damage to the functional polymer coat and segregation of pellets from other excipients during the tableting process. This study was designed to investigate the impact of porous pellets as cushioning agent without issues related to segregation while tableting. Different drying techniques were applied to produce microcrystalline cellulose (MCC) pellets with various porosities. Sodium chloride was also added to the pellet formulation as a pore forming agent to generate a porous skeleton after production and aqueous extraction. The pellets fabricated were characterized for their porosity, crushing strength and yield pressure. Tablets were prepared using unlubricated pellets and their tensile strengths determined. Blends containing polymer-coated pellets and cushioning pellets of various porosities were compacted at different compaction pressures. The porous pellets exhibiting the best cushioning effect were used for MUPS tableting at different compression speeds with both gravity and force feeders. The findings from this study showed that pellet porosity was highest when drying was carried out in a freeze dryer, followed by fluid bed and least porous from the oven. There was an inverse relationship between pellet porosity and strength. The protective effect of cushioning pellets was mainly dependent on their porosity. The porosity of pellets manufactured by leaching NaCl from MCC-NaCl (1:1) pellets were 2.14-, 2.57- and 4.88-fold higher than that of MCC PH101 only pellets for oven, fluid bed and freeze dried pellets, respectively. Although the porosity of MCC PH101-NaCl (1:3) pellets was highest, they exhibited less cushioning effect than MCC PH101-NaCl (1:1). It was inferred that a good balance between porosity and bulk density of cushioning pellets was essential to be effective at protecting the coated pellets from damage during compaction. Compared with MUPS tablets prepared using unprocessed MCC PH105, the tablets prepared with the porous freeze dried MCC PH101 (NaCl fraction leached) pellets had improved drug content uniformity and were mechanically stronger.

Cushioning pellets based on microcrystalline cellulose - Crospovidone blends for MUPS tableting.

Compaction of multiple-unit pellet system (MUPS) tablets has been extensively reported to be potentially challenging. Thus, there is a need for non-segregating cushioning agents to mitigate the deleterious effect of the compaction forces. This study was designed to investigate the use of porous pellets as cushioning agents using different drying techniques to prepare pellets of various porosities and of different formulations. The pellets fabricated were characterized for their porosity and crushing strength. Subsequently, MUPS tablets were prepared using blends of polymer-coated pellets and custom-designed cushioning pellets by compacting at different pressures. The effects of pellet volume fraction and dwell time on the pellet coat damage, as well as the tensile strength of the resultant MUPS tablets were also investigated. Compacts with coated pellet volume fraction of 0.21 exhibited the best cushioning effect when tableted at different compression speeds with both gravity and force feeders. The findings from this study showed that cushioning pellet porosity was highest when drying was carried out by freeze drying, followed by fluid bed drying and oven drying. There was an inverse relationship between cushioning pellet porosity and strength. The tensile strength of tablets prepared from freeze dried pellets was highest. The protective effect of the cushioning pellets was principally dependent on their porosity. Also, pellet volume fraction in the compacts and compaction pressure used had remarkable effect on pellet coat damage. When unprocessed powders were compacted by automatic die filling, capping and lamination problems were observed. However, tablets of reasonable quality were made with the cushioning pellets. Freeze dried pellets containing crospovidone were found to be promising as cushioning agents and had enabled the production of MUPS tablets even at higher compaction pressures, beyond the intrinsic crushing strength of the coated pellets.

Insights on the role of excipients and tablet matrix porosity on aspirin stability.

Excipient-moisture interaction can be a critical attribute in determination of product stability. This study aimed to investigate influence of integrating excipients having different moisture interaction into moisture sensitive drug formulations. Aspirin was formulated with maize starch (MS), microcrystalline cellulose (MCC) and calcium hydrogen phosphate dihydrate (DCP). The excipients were evaluated for their inherent moisture content and water activity. Tablets fabricated at different compression pressures were exposed to 40 °C, 75% relative humidity for a stipulated period before analyzing for aspirin degradation. The results revealed that while MS had higher moisture content, the water activity was relatively low. Consequently, MS tablets had lower aspirin degradation than MCC and DCP tablets. In contrast, high water activity of DCP resulted in greater aspirin degradation. This was despite the low moisture content of DCP. Influence of tablet porosity on aspirin degradation was minimal. This illustrated the fugacity of moisture, possessing high thermodynamic activity and physical spatial delimitation would not suppress its distribution. The findings suggested that excipients possessing high water retentive capacity could potentially be useful as internal tablet desiccants by acting as a moisture scavenger. This study also highlights the importance of water activity in preformulation studies related to the choice of excipients.

A mechanistic understanding of compression damage to the dissolubility of coated pellets in tablets.

Damage to the drug diffusion coat barrier of controlled release pellets by the compaction force when preparing multiple-unit pellet system tablets is a major concern. Previous studies have shown that pellets located at the tablet axial and radial peripheral surfaces were more susceptible to damage when compacted due to the considerable shear encountered at these locations. Hence, this study was designed to assess with precision the impact of pellet spatial position in the compact on the extent of coat damage by the compaction force via a single pellet in minitablet (SPIM) system. Microcrystalline cellulose (MCC) pellet cores were consecutively coated with a drug layer followed by a sustained release layer. Chlorpheniramine maleate was the model drug used. Using a compaction simulator, the coated pellets were compacted singly into 3 mm diameter SPIMs with MCC as the filler. SPIMs with individual pellets placed in seven positions were prepared. The uncompacted and compacted coated pellets, as SPIMs, were subjected to drug release testing. The dissolution results showed that pellets placed at the top-radial position were the most susceptible to coat damage by the compaction force, while pellets positioned within the minitablet at the middle and upper quadrant positions showed the least damage. The SPIM system was found to be effective at defining the extent of coat damage to the pellet spatial position in the compact. This study confirmed that coated pellets located at the periphery were more susceptible to damage by compaction, with pellets located at the top-radial position showing the greatest extent of coat damage. However, if the pellet was completely encrusted by the cushioning filler, coat damage could be mitigated. Further investigations were directed at how the extent of coat damage impacted drug release. Interestingly, small punctures were found to be most detrimental to drug release whilst coats with large surface cuts did not completely fail. A damaged pellet coat has some self-sealing ability and failure is not total. Thus, this study provides a deeper understanding of the consequence of coat damage to drug release when sustained release coated pellets are breached.

De-risking excipient particle size distribution variability with automated robust mixing: Integrating quality by design and process analytical technology.

BACKGROUND: Particle size distribution (PSD) variability in excipients affects mixing. In response, manufacturers rely on raw material control and rigidly defined process parameters to achieve quality. However, this status quo is costly; and diverges from regulatory exceptions for process robustness. Although robustness improves cost and material usage efficiency, it remains under-adopted. METHOD: To address this gap, a robust batch mixing operation that mitigated the impact of PSD variability was evaluated, with blends comprising chlorpheniramine, microcrystalline cellulose and lactose. PSD of lactose was varied to simulate commercially-relevant variability. Due to PSD-induced rheological variations, the blends had different optimal mixing speeds. For the automation study, near infrared (NIR) spectroscopy; process optimization and endpoint detection algorithms; and control hardware were integrated within a cluster of software environments. NIR spectroscopy was employed for in-line PSD characterization and blend monitoring, to modulate mixing speed and detect endpoint (feedforward and feedback control). RESULTS: NIR spectroscopy rapidly detected PSD variations by the 6th-9th rotations, to activate feedforward control, which mitigated the effect of PSD variability and reduced the mixing time by 13-34%. Endpoints were correctly detected. PSD variations and blend homogeneity were accurately predicted (relative standard error of prediction ≤ 2%). CONCLUSION: The automated robust mixing operation was successful. Pertinently, NIR spectrometer can be adopted for multimodal sensing. Its applicability for production-driven characterization of raw materials in batch and continuous pharmaceutical processing should be further explored. Lastly, this study laid the groundwork for end-to-end implementation of process analytical technology in robust batch processing.