A study on in-line tablet coating--the influence of compaction and coating on tablet dimensional changes.

Prior to coating, tablets are usually stored for a definite period to enable complete strain recovery and prevent subsequent volumetric expansion-related coating defects. In-line coating is defined as the coating of tablets immediately after compaction. In-line coating will be expected to improve manufacturing efficiencies. In this study, the possibility of in-line coating was studied by evaluating the influence of compaction and coating on tablet dimensional changes. The use of tapered dies for compaction was also evaluated. Two types of tablet coaters which presented different coating environments, namely the Supercell™ coater and pan coater, were employed for coating. The extent of tablet dimensional changes was studied in real time using optical laser sensors in a controlled environment. After compaction, tablet dimensional changes were found to be anisotropic. In contrast, coating resulted in isotropic volume expansion in both the axial and radial directions. Pan coating resulted in significantly greater tablet dimensional changes compared to Supercell™ coating. There was no significant difference in dimensional changes of tablets coated in line or after complete viscoelastic strain recovery for Supercell™ coating. However, significantly different dimensional changes were observed for pan coating. The use of tapered dies during compaction was found to result in more rapid viscoelastic strain recovery and also significantly reduced tablet dimensional changes when tablets were immediately coated after compaction using the pan coater. In conclusion, the Supercell™ coater appeared to be more suitable for in-line tablet coating, while tapered dies were beneficial in reducing tablet dimensional changes when the pan coater was employed for in-line coating.

Cone milling of compacted flakes: process parameter selection by adopting the minimal fines approach.

Cone mill was well studied for milling of wet agglomerates. This study evaluated the effects of various process parameters of cone milling roller compacted flakes on the granules produced. Impeller sidearm shapes, screen surface profiles and impeller speeds were studied. Impeller speed was found to play a major role in determining the granule attributes. Besides this, median size, size distribution and percent fines of a milled granule population were mainly determined by the size reduction mechanisms of different impellers and screens. Pre-breaking followed by shearing and slicing of flakes inside the milling chamber was primarily responsible for determining the size, size distribution and percent fines of milled granules. The pre-breaking action could be achieved using teethed round sidearm impeller and lowered the need for screen-based size reduction, thus generating less fines. The shearing and slicing of flakes due to the raised impaction edges of the grater screen also helped to minimize the production of fines. Therefore, the lowest percentage of fines was observed when the teethed round sidearm impeller was used with a grater screen. The results indicated that fines can be reduced considerably with the judicious selection of a suitable impeller and screen combination in the cone mill.

The butterfly effect: a physical phenomenon of hypromellose matrices during dissolution and the factors affecting its occurrence.

A phenomenon was observed for the behavior of hypromellose matrices during dissolution. The tablet laminated radially, with both edges curled outwards, forming a "butterfly" shape. The butterfly effect is thus coined to describe this behavior. Due to the flamboyant shape assumed by the hydrated matrix, the apparent surface area for drug release was significantly increased. This study attempted to elucidate mechanistically the cause of this butterfly effect. Two formative mechanisms were proposed based on the behavior of moving solvent fronts and the anisotropic expansion of materials in solution. It was hypothesized that the particle size of hypromellose, applied compaction force used and proportions of both insoluble and soluble excipients contributed to the butterfly effect. The influence of the expanded shape on the mechanism and rate of drug release was also investigated. Matrix formulation was an important factor. Greater drug release was observed when the butterfly-shaped hydrated matrix was formed. The drug release profiles generally fitted the Higuchi and Korsmeyer-Peppas equations, indicating a combination of both diffusion and erosional drug release mechanisms. A combination of both fine and coarse hypromellose size fractions and adequate compaction force (more than 3 kN) were necessary for the manifestation of the butterfly effect.

Comparative study of non-destructive methods to quantify thickness of tablet coatings.

The Supercell coater is a newly introduced coater which utilizes air fluidization for tablet coating. The aim of this study was to define a suitable, fast and non-destructive method for the quantification of coat thickness for Supercell-coated tablets. Various coat thickness characterization methods were carried out on tablets coated at different process conditions. These include the use of optical microscopy, micrometer, X-ray fluorescence (XRF), Raman and near-infrared (NIR) spectroscopy. Coat thicknesses obtained from direct measurements were used to calibrate the spectral data from spectroscopic methods for model generation. The models were subsequently validated to evaluate their prediction capabilities, especially the ability to differentiate tablets coated at different conditions. XRF spectroscopy was viewed to be more suitable for the assessment of process yield and efficiency but both Raman and NIR spectroscopy were shown to be more appropriate methods for the rapid prediction and evaluation of coat thickness. However, only Raman spectroscopy was able to differentiate tablets coated under different conditions accurately. In conclusion, direct thickness measurements were more time-consuming but provided assured coat thickness data. On the other hand, XRF, Raman and NIR spectroscopy methods were viable alternatives to provide complementary information for the study of tablet coatings.

Calibration sampling paradox in near infrared spectroscopy: a case study of multi-component powder blend.

The objective of this study was to illustrate the sampling paradox resulting from the different strategies of spectral acquisition while preparing and implementing the calibration models for prediction of blend components in multi-component cohesive blends. A D-optimal mixture design was used to create 24 blending runs of the formulation consisting of chlorpheniramine maleate, lactose, microcrystalline cellulose and magnesium stearate. Three strategies: (a) laboratory mixing and static spectral acquisition, (b) IBC mixing and static spectral acquisition and (c) IBC mixing and dynamic spectral acquisition were investigated for obtaining the most relevant and representative calibration samples. An optical head comprising a sapphire window mounted on the lid of the IBC was used for static and dynamic NIR spectral acquisition of the powder blends. For laboratory mixed samples, powders were blended for fixed period of 30 min and later on scanned for NIR spectra. For IBC mixed blends, the spectral acquisition was carried out in-line for 2 min and stopped for static spectral acquisition. The same cycle was repeated for the next 28 min. Partial least square (PLS) calibration models for each component were built and ranked according to their calibration statistics. Optimal calibration models were selected from each strategy for each component and used for in-line prediction of blend components of three independent test runs. Although excellent statistics were obtained for the PLS models from the three strategies, significant discrepancies were observed during prediction of the independent blends in real time. Models built using IBC mixed blends and dynamic spectral acquisition resulted in the most accurate predictions for all the blend components, whereas models prepared using static spectral acquisition (laboratory mixed and IBC) showed erroneous prediction results. The prediction performance differences between the models obtained using the different strategies could be explained in the context of relevancy and representative sample collection at the initial stage of calibration model building.

In-line quantification of drug and excipients in cohesive powder blends by near infrared spectroscopy.

This work was aimed at investigating the utility of near infrared (NIR) spectroscopy for simultaneous in-line quantification of drug and excipients in cohesive powder blends in a bin blender. A model formulation containing micronized chlorpheniramine maleate (microCPM), lactose, microcrystalline cellulose (MCC) and magnesium stearate (MgSt) was selected for the blending study. An optical head comprising a sapphire window mounted on the lid of the bin was used to collect in-line NIR spectral data of the powder blends. Validated partial least square (PLS) calibration models were used to quantify each component from the NIR spectra of the blends. Additionally, effects of premixing by sieving and high shear mixing and use of an internal prism fixed within the bin on the mixing performance of each component were studied. The statistical results obtained for PLS calibration models and their validation showed the sensitivity of NIR for accurate quantification of blend components. The blend prepared with high shear premixing and with prism achieved uniformity more rapidly than that with high shear premixing but without prism during blending in a bin blender. Premixing using sieving proved to be inadequate for uniform mixing of the blend components as none of the components except MgSt achieved uniform distribution after the preset blending time when blended in the bin blender. This study demonstrated that by high speed sampling and rapid spectral acquisition, distribution of individual blend components can be assessed with high accuracy during blending. Furthermore, high shear premixing facilitated rapid distribution and uniformity achievement of blend components. This technique may be used to monitor the relative distribution of individual blend components in real time and thus, to assess the performance of a bin blender for mixing of cohesive multi-component powder blends during development and production.

A study on microwave-induced melt granulation in a single pot high shear processor.

Microwave-induced high shear melt granulation was compared with conventional melt granulation performed in the same processor. Admixtures of lactose 200M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350. Different heating mechanisms in the two processes necessitated the use of different parameters for process monitoring and control. Mixer power consumption was suitable for monitoring agglomerate growth under microwave-induced heating. Product temperature was a better indicator of agglomeration propensity in conventional melt granulation. These were attributed to the disparities in heat acquisition rates and heating uniformities of the powders as well as variation in baseline mixer power consumption between the two processes.

Microwave-assisted drying of pharmaceutical granules and its impact on drug stability.

The advent of microwave technology has intensified the search for pharmaceuticals amenable to microwave processing. This study investigated the influences of powder load, diluent particle size and amount of granulating liquid employed on the microwave-assisted drying and stability of acetylsalicylic acid (ASA)-loaded granules in a single pot high shear processor. Powder load affected the profiles, rate and extent of drying. Drying was more dependent on the size and structural properties of granules rather than their surface areas as heat was generated volumetrically. Increased granule size brought about by increasing the size of diluent particles and amount of granulating liquid resulted in higher drying rates. Drug stability was negatively correlated to the drying time of granules.

Impact of cross-linker on alginate matrix integrity and drug release.

Sodium alginate, a biopolymer, was employed in the formulation of matrix tablets. They cracked or laminated at acidic pH, compromising their dissolution performance. Improved mechanical strength and reduced barrier permeability of calcium alginate gel provided the rationale for cross-linking the alginate matrix to sustain drug release. Studies had suggested that the incorporation of soluble calcium salts in alginate matrix tablets could sustain drug release at near-neutral pH due to in situ cross-linking. However, results from the present study showed otherwise when gastrointestinal pH conditions were simulated. Significant reduction in drug release rate was only observed when an external calcium source was utilized at low concentration. High calcium ion concentrations caused matrix disintegration. In contrast, matrices pre-coated by calcium alginate could sustain drug release at pH 1.2 followed by pH 6.8 for over 12h. The presence of cross-linked barrier impeded matrix lamination and preserved matrix structure, contributing to at least three-fold reduction in drug release at pH 1.2. Zero order release as well as delayed burst release could be achieved by employing appropriate grade of alginate and cross-linking conditions.

Drying efficiency and particle movement in coating--impact on particle agglomeration and yield.

The purpose of this study was to determine the influences of drying efficiency and particle movement on the degree of agglomeration and yield of pellets coated under different conditions. Thermodynamic conditions were varied using different inlet air temperatures and airflow rates, fluid dynamics were varied using different airflow patterns and air velocities, and two sizes of pellets were coated at different airflow rates and partition gaps. Agglomeration was minimized when all the moisture introduced into the system was removed by the drying air. Excessively dry conditions led to increased loss of yield due to spray-drying effect and attrition. Fluid dynamics were still important even with adequate drying, as the degree of agglomeration was relatively higher in the non-swirling airflow of Wurster coating than in the swirling airflow of precision coating. Increasing air velocities increased pellet velocities, resulting in lower degrees of agglomeration. Hence, agglomeration due to fluid dynamics was attributed to differences in pellet velocities, pellet proximity and pellet trajectories within the partition column. Smaller pellets agglomerated primarily from inadequate drying and not due to inadequate opportunities for particle movement. Larger pellets were more affected by the partition gap due to restriction of their movement through the partition gap. Hence, both thermodynamics and fluid dynamics were found to be important in minimizing agglomeration and ensuring quality coated products.

Use of swirling airflow to enhance coating performance of bottom spray fluid bed coaters.

As there is strong interest in coating increasingly smaller particles or pellets for use in compacted dosage forms, there is a need for better small particle coating systems. This study explored the use of swirling airflow to enhance the performance of the bottom spray coating system. Firstly, pellet coating in the non-swirling airflow of conventional Wurster coating was compared with that of swirling airflow in precision coating under standardized conditions. Secondly, precision coating was studied in greater details at different airflow rates (60-100m(3)/h) and partition gaps (6-22mm). Precision coating was found to have higher Reynolds numbers (Re) than Wurster coating, indicating higher turbulence. It produced coated pellets of better properties than Wurster coating, having less agglomeration and gross surface defects, more uniform coats, increased flow and tapped density, and slower drug release. Higher surface roughness did not affect the yield. In precision coating, increasing airflow rates decreased the degree of agglomeration but had minimal effect on pellet quality attributes (colour intensity, colour uniformity and surface roughness) and yields. Increasing partition gaps increased the degree of agglomeration proportionally, but this effect was small. However, greater changes in yield, surface roughness, colour intensity and colour uniformity were detected. This study showed that precision coating, while having a higher drying ability, was able to maintain the same yield and produce coated pellets with superior quality compared to Wurster coating. In precision coating, airflow rate had greater influence on the drying of pellets while partition gap had greater influence on pellet quality attributes.

Feasibility of eliminating premixing for the production of pellets in a rotary processor.

This current study aims to explore the feasibility of eliminating the premixing step for making pellets in a rotary processor. Microcrystalline cellulose (MCC) and lactose were used as starting materials. They could be loaded into the rotary processor separately using three different loading configurations (Methods I, II, and III) or as MCC:lactose blend, which was prepared in the separate mixer prior to loading (Method IV). Physical properties of the pellets prepared in Methods I-III were evaluated and compared against those prepared using a premixed blend (Method IV). The effects of loading configuration on pellet quality can be assessed by comparing the pellets prepared in Methods I, II, and III. Physical characterization of pellets included mean size, size distribution, oversized fraction, and shape. No significant difference in pellet properties could be attributed to the effect of premixing. Pellet properties were not significantly affected by the different loading configurations either. This study demonstrated that homogeneous powder blends are not required for the production of pellets in rotary processing. The tumbling action of the powders at the start of rotary processing is sufficient to ensure adequate powder mixing. However, it may be judicious to cofeed the different powders to achieve some preliminary mixing during loading under extreme processing conditions.

Torque rheological parameters to predict pellet quality in extrusion-spheronization.

This study explored the feasibility of predicting the quality of microcrystalline cellulose (MCC) pellets prepared by extrusion-spheronization using torque rheological characterization. Rheological properties of eleven MCC grades as well as their binary mixtures with lactose (3:7) at various water contents were determined using a mixer torque rheometer (MTR). Derived torque parameters were: maximum torque and cumulative energy of mixing (CEM). CEM values of MCC powders (CEM((MCC))) could be attributed to their physical properties such as crystallinity, V(low P) and V(total) (volumes of mercury intruded in their pores at low pressure and the total intrusion volume), bulk and tapped densities. For both MCC powders and their binary mixtures, strong correlation was observed between their torque parameters and the properties of their pellets formed with 30 and 35% (w/w) water. Since this relationship was valid over a broad water content range, rheological assessment for pre-formulation purposes need not be performed at optimized water contents. These results demonstrated the usefulness of torque rheometry as an effective means of comparing and evaluating MCC grades especially when substitution of equivalent grades is encountered. In so doing, the tedious and expensive pre-production (pre-formulation and optimization) work can be considerably reduced.

Investigation of wetting behavior of nonaqueous ethylcellulose gel matrices using dynamic contact angle.

PURPOSE: This study reports the development of a method based on dynamic contact angle to investigate the wetting behavior of non-aqueous ethylcellulose (EC) gel matrices intended for topical drug delivery. METHODS: Non-aqueous gel matrices were prepared from the three fine particle grades of EC and propylene glycol dicaprylate/dicaprate. Dynamic contact angle measurements of sessile drops of water and isopropylmyristate (IPM) on EC gel matrices were performed using a dynamic contact angle analyzer equipped with axisymmetric drop shape analysis of the sessile drop images. Gel density was determined by weighing known volumes of gel samples. RESULTS: The EC gel matrices were wetted by both water and IPM, with much higher wettability by the latter. Increased EC concentration and polymeric chain length decreased the extent and rate of wetting. Linear correlation was observed between wetting parameters and rheological as well as mechanical properties of EC gel matrices. CONCLUSIONS: The EC gel matrices exhibited both hydrophilic and lipophilic properties, with predominance of the latter. The extent and rate of wetting was governed by a balance of chemical and physical characteristics of the gel. EC gel matrices showed desirable wetting behavior in their function as a moisture-barrier, bioadhesive and vehicle for topical drug delivery.

Investigation of the release of aspirin from spray-congealed micro-pellets.

The release behaviour of aspirin from spray-congealed hydrogenated soybean oil micro-pellets of different sizes was studied. The purpose of this study was to investigate the effect of particle size of micro-pellets on the drug release profile and mechanism. Micro-pellets produced were sieved into several fractions and their drug content and dissolution profiles in two media were determined. The dissolution mechanism was studied by fitting the data to release kinetic models. Micro-pellets with high encapsulation efficiency were successfully produced. The micro-pellets were able to sustain the release of aspirin in pH 1.2 and pH 6.8 dissolution media. As particle size of micro-pellets increased, the drug release rate decreased. The drug release mechanism was affected by the size of micro-pellets. Micro-pellets in the range of 90-250 microm tended to follow the first order or Higuchi model. However, micro-pellets in the range of 250-355 microm were found to follow zero-order release model. This result showed that drug release could be modified by controlling the size of micro-pellets and that controlled release of drug might be achieved by using larger size micro-pellets.

Effect of oil loading on microspheres produced by spray drying.

Oil-loaded microspheres were produced by spray drying emulsions consisting of fish oil and modified starch suspensions with different oil loadings. The emulsion stability was assessed by oil droplet size analysis. Microspheres were characterized in terms of size, morphology, yield and microencapsulation efficiency. It was found that an increase in oil loading resulted in emulsions containing larger oil droplets. This corresponded with larger mean microsphere diameters and rounder microspheres. However, high oil loadings produced lower yields and affected microencapsulation efficiencies.

Influence of partially cross-linked alginate used in the production of alginate microspheres by emulsification.

Spherical and discrete calcium alginate microspheres had been produced by the emulsification technique. The microencapsulation process was highly efficient, but drug release from microspheres was rapid. A more orderly chain arrangement of the polymeric chains would give rise to a stronger and less permeable matrix capable of sustaining drug release. Therefore, the potential of using partially cross-linked alginate in the production of microspheres by emulsification was explored. The size and roundness of the microspheres, its drug content and drug release property were determined. The more viscous alginate solutions when reacted with more calcium salt added resulted in larger microspheres produced. Microspheres made from partially cross-linked alginate exhibited lower drug content and higher T75% values in drug release studies. This was due to decreased flexibility of the polymer chains which were partially held together by calcium ions, reducing subsequent interaction with the calcium ions resulting in lower drug entrapment efficiency and a more permeable microsphere matrix.

Development of novel nonaqueous ethylcellulose gel matrices: rheological and mechanical characterization.

PURPOSE: This study reports the rheological and mechanical characterization of novel non-aqueous ethylcellulose gel matrices intended for topical drug delivery. An attempt was also made to explain the molecular interaction within the gel systems from a molecular conformational approach. METHODS: Nonaqueous gel matrices were prepared from three fine particle grades of ethylcellulose and propylene glycol dicaprylate/dicaprate. Continuous and oscillatory shear rheometry was performed using a cone-and-plate rheometer and mechanical characterization was performed using a universal tensile tester. RESULTS: The gel matrices exhibited prominent viscoelastic behaviour, yield stress and thixotropy. Rheological and mechanical properties showed significant upward trends with increased polymeric chain length and polymer concentrations. Good linear correlations were obtained between rheological and mechanical properties. The solvent molecular conformation was found to play a role in affecting the formation of gel networks via intermolecular hydrogen bonding between ethylcellulose polymer chains. CONCLUSIONS: Ethylcellulose was successfully formulated as a nonaqueous gel with propylene glycol dicaprylate/dicaprate. The novel nonaqueous gel exhibited rheological profiles corresponding to a physically cross-linked three dimensional gel network, with suitable mechanical characteristics for use as a vehicle for topical drug delivery. Molecular conformation of the solvent was found to influence the molecular interactions associated with formation of ethylcellulose gel networks.

Roller compaction of crude plant material: influence of process variables, polyvinylpyrrolidone, and co-milling.

Roller compaction of a milled botanical (Baphicacanthus cusia) with and without a binder, polyvinylpyrrolidone (PVP) was conducted. Effects of co-milling on binder function and flowability of the powder blend was also investigated. Flakes were comminuted, and the size and size distribution, friability, Hausner ratio, and Carr index of the granulations were determined. Crude herb should be reduced to a suitable size for it to be successfully roller compacted. Larger-sized and less friable granules were obtained with decreasing roller speed. Addition of PVP affected the flowability and binding capacity of the herbal powder blend, which influenced size and friability of the granules. Co-milling of PVP with the herbal powder enhanced the flow of the blends and the effectiveness of the binder, which contributed favorably to the roller-compacted product. Roller compaction is a convenient and cost-effective granulating technique suitable for milled botanicals. Co-milling can be used to improve the properties of roller-compacted products.

Wet spheronization by rotary processing--a multistage single-pot process for producing spheroids.

Spheronization is an agglomerative size enlargement process for producing spherical agglomerates that have many technological and therapeutical advantages. Rotary processing is an efficient multistage, single-pot spheroid production method. The rotary processor can be used for spheroid production, drying as well as coating. In the course of spheroid production, centrifugal, fluidizing, and gravitational forces act upon the product from different directions and collectively contribute to the spheroid formation process during rotary processing. The outcome of the process depends on the complex interactions between the equipment, formulation, and process variables.