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The deformulation stage of original drug products, which includes the quantification of critical excipients, is crucial for the successful development of generic drug products of solid dosage form. Sodium lauryl sulphate (SLS) belongs to the group of critical excipients due to its influence on the bioavailability of drugs, such as metformin. The purpose of this work is to carry out a feasibility study in order to develop a simple, economical, and robust analytical method for the quantification of SLS in metformin-containing tablets after their dissolution in water. Firstly, SLS is extracted with chloroform in acidic conditions, followed by the addition of methylene blue (MB) in order to form a SLS-MB ion pair, which is then measured photometrically at a wavelength of 651 nm. Additionally, interference from matrix components (excipients and APIs) was assessed, and it was found that metformin also forms a blue complex; therefore, this specific extraction method was developed. Other matrix components did not interfere with SLS determination. This method shows a well-estimated precision of 3.3% and accuracy of 5%, a calibration linearity of R2 = 0.99990, and a working range of 0.38 µg/mL to 10 µg/mL of SLS in water. The midpoint of the calibration graph corresponds to the concentration of SLS obtained by dissolving a single tablet in 1 L of water. This method seems appropriate for total SLS determination in tablets and can be applicable for deformulation. [ABSTRACT FROM AUTHOR]

The deformulation stage of original drug products, which includes the quantification of critical excipients, is crucial for the successful development of generic drug products of solid dosage form. Sodium lauryl sulphate (SLS) belongs to the group of critical excipients due to its influence on the bioavailability of drugs, such as metformin. The purpose of this work is to carry out a feasibility study in order to develop a simple, economical, and robust analytical method for the quantification of SLS in metformin-containing tablets after their dissolution in water. Firstly, SLS is extracted with chloroform in acidic conditions, followed by the addition of methylene blue (MB) in order to form a SLS-MB ion pair, which is then measured photometrically at a wavelength of 651 nm. Additionally, interference from matrix components (excipients and APIs) was assessed, and it was found that metformin also forms a blue complex; therefore, this specific extraction method was developed. Other matrix components did not interfere with SLS determination. This method shows a well-estimated precision of 3.3% and accuracy of 5%, a calibration linearity of R2 = 0.99990, and a working range of 0.38 µg/mL to 10 µg/mL of SLS in water. The midpoint of the calibration graph corresponds to the concentration of SLS obtained by dissolving a single tablet in 1 L of water. This method seems appropriate for total SLS determination in tablets and can be applicable for deformulation.

In this work, the influences of polymers (HPMC E3, PEG 6000, PVP K25, PVP K30), temperature, stirring speed and polymer mass fraction on the oxaprozin (OXA) dissolution profiles were measured by a United States Pharmacopeia (USP) Ⅱ dissolution apparatus. The two-step chemical potential gradient model combined with the interfacial steady-state mass transfer model as well as PC-SAFT (perturbed-chain statistical associating fluid theory) were used to analyze the dissolution mechanism of OXA under different conditions. The presence of polymer could promote the surface reaction of OXA while temperature and stirring speed have different influences on the surface reaction and diffusion. The diffusion boundary layer thickness δ of OXA tablets increases with the increase of temperature and decreases with the increase of stirring speed. Based on the obtained surface reaction rate constant k s and diffusion rate constant k d , the dissolution profiles with high accuracy compared with the experimental data. [Display omitted] • Calculating the concentration at solid-liquid interface by mass transfer model. • The presence of excipients affects the solubility and dissolution mechanism. • Temperature and stirring speed affect the dissolution mechanism. • Surface reaction and diffusion work together to control dissolution. [ABSTRACT FROM AUTHOR]

[Display omitted] • Optical coherence tomography for the estimation of. • Tablet porosity. • Tablet hardness. • Real-time in-line OCT measurements and porosity prediction directly after the tablet press. In-line monitoring of critical quality attributes (CQAs) during a tableting process is an essential step toward a real-time release strategy. Such CQAs can be the tablet mass, the API content, dissolution, hardness and tensile strength. Since dissolution testing is laborious and time-consuming and cannot be performed in-line, it is desirable to replace dissolution testing with predictive models based on other CQAs that affect the dissolution characteristics, such as the tablet porosity and hardness. Traditionally, porosity is determined offline via gas adsorption methods or other techniques, such as Terahertz spectroscopy or gas in scattering media absorption spectroscopy. Tablet hardness is typically established using a hardness tester. While these destructive tests can readily be performed at-line, they have limited applicability in in-line settings for a high-percentage inspection. Optical coherence tomography (OCT) has recently been proposed as a possible tool for determining quality attributes. This work describes the first application of OCT for the prediction of tablet porosity and hardness. OCT measurements of tablets produced in a ConsiGma 25™ tableting line and a Stylcam 200R compaction simulator in several compaction force settings were performed and correlated with the porosity and hardness. It was demonstrated that OCT can easily be installed in-line and provide real-time information about critical material attributes. These insights confirm the applicability of OCT as a real-time quality control tool and its potential to replace time-consuming and destructive offline measurements. [ABSTRACT FROM AUTHOR]

We propose a two-stage reduced-order model (ROM) of pharmaceutical tablet dissolution that is comprised of (i) a mechanistic dissolution function of the active pharmaceutical ingredient (API) and (ii) a tablet wetting function. The former is derived from a population balance model, using a high-resolution finite volume algorithm for a given API crystal size distribution and dissolution rate coefficient. The latter is obtained from the mechanistic understanding of water penetration inside a porous tablet, and it estimates the rate at which the API is exposed to the buffer solution for a given formulation and the dimensions of the tablet, contact angle, and surface tension between the solid and liquid phases, liquid viscosity, and mean effective capillary radius of the pore solid structure. In turn, the two-stage model is mechanistic in nature and one-way coupled by means of convolution in time to capture the start time of the API dissolution process as water uptake, swelling, and disintegration take place. The two-stage model correlates dissolution profiles with critical process parameters (CPPs), critical material attributes (CMAs), and other crucial critical quality attributes (CQAs). We demonstrate the model's versatility and effectiveness in predicting the dissolution profiles of diverse pharmaceutical formulations. Specifically, we formulate and fabricate acetaminophen and lomustine solid tablets using different API content and size distributions, characterize their dissolution behavior, and estimate capillary radius as a function of tablet porosity. The estimations generated by the proposed models consistently match the experimental data across all cases investigated in this study. [Display omitted] [ABSTRACT FROM AUTHOR]

Real-time release testing (RTRt) of tablet dissolution can significantly improve manufacturing efficiency along with the adoption of continuous manufacturing in the pharmaceutical industry. To assure product quality without destructive testing, models for RTRt should be sufficiently reliable and robust. Whereas mechanistic models have merits of broader applicability and interpretability, data-driven models have been common approaches due to computational speed. This paper discusses challenges and opportunities in the application of mechanistic models for dissolution testing to enable RTRt of solid dosage. After a comprehensive literature review on mechanistic dissolution models and RTRt, the potential benefits and challenges of mechanistic models are presented. Compared to data-driven models, mechanistic models require less experimental data that can reduce time and cost for RTRt development. However, to enable the implementation of mechanistic models in RTRt, computational time should be short either by using a simple mechanistic model or by applying surrogate models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, a compartmental disintegration and dissolution model is proposed for the prediction and evaluation of the dissolution performance of directly compressed tablets. This dissolution model uses three compartments (Bound, Disintegrated, and Dissolved) to describe the state of each particle of active pharmaceutical ingredient. The disintegration of the tablet is captured by three fitting parameters. Two disintegration parameters, β 0 and β t , 0 , describe the initial disintegration rate and the change in disintegration rate, respectively. A third parameter, α , describes the effect of the volume of dissolved drug on the disintegration process. As the tablet disintegrates, particles become available for dissolution. The dissolution rate is determined by the Nernst-Brunner equation, whilst taking into account the hydrodynamic effects within the vessel of a USP II (paddle) apparatus. This model uses the raw material properties of the active pharmaceutical ingredient (solubility, particle size distribution, true density), lending it towards early development activities during which time the amount of drug substance available may be limited. Additionally, the strong correlations between the fitting parameters and the tablet porosity indicate the potential to isolate the manufacturing effects and thus implement the model as part of a real-time release testing strategy for a continuous direct compression line. [Display omitted] [ABSTRACT FROM AUTHOR]

• A continuous high-shear mixer granulator with enhanced process performance. • Comprehensive analysis of the relationship between CPPs and CQAs. • Revealed tablet dissolution mechanisms associated with physical microstructures. • Explicated correlation between tablet drug agglomerate size and release kinetics. Over the past decade, continuous wet granulation has been emerging as a promising technology in drug product development. In this paper, the continuous high-shear mixer granulator, Lӧdige CoriMix® CM5, was investigated using a low-dose formulation with acetaminophen as the model drug. Design of experiments was deployed in conjunction with multivariate data analysis to explore the granulator design space and comprehensively understand the interrelation between process parameters and critical attributes of granules and tablets. Moreover, several complementary imaging techniques were implemented to unveil the underlying mechanisms of physical and chemical microstructure in affecting the tablet performance. The results indicated that L/S ratio and impeller speed outweighed materials feeding rate in modifying the granule and tablet properties. Increasing the degree of liquid saturation and mechanical shear input in the granulation system principally produced granules of larger size, smaller porosity, improved flowability and enhanced sphericity, which after compression generated tablets with slower disintegration process and drug release kinetics due to highly consolidated physical microstructure. Besides, in comparison to batch mixing, continuous mixing integrated with a conical mill enabled better powder de-agglomeration effect, thus accelerating the drug dissolution with increased surface area. [ABSTRACT FROM AUTHOR]

• A workflow was developed utilizing X-ray microcomputed tomography and convolutional neural network-based image segmentation to image and obtain physical parameters of enterically-coated mini-tablets non-destructively • Average enteric coat thickness and micro-crack volume were obtained for individual mini-tablets • The imaged mini-tablets were then subjected to two-stage dissolution studies to evaluate the performance of the enteric coat and pre-defined dissolution criteria in the buffer stage • Strong correlations were established between the physical parameters of the mini-tablets and the two-stage dissolution performance • The correlations enabled prediction of dissolution performance utilizing non-destructive XRCT imaging data Mini-tablets (MTs) have been utilized as an alternative to monolithic tablets due to their ease of use for pediatric populations, dose flexibility and tailoring of drug release profiles. Similar to monolithic tablets, MTs can develop film coat and internal core defects during manufacturing processes that may adversely affect their dissolution performance. The use of x-ray computed microtomography (XRCT) is well documented for monolithic tablets as a means of identifying internal defects, but applications to MTs have not been well studied. In this study, we have developed a workflow that analyzes reconstructed XRCT images of enteric-coated mini-tablets using deep learning convolutional neural networks. This algorithm was utilized to extract key physical features of individual MTs, such as micro-crack volume and enteric coat thickness. By performing dissolution studies on individual MTs, correlations were established based on the physical parameters obtained by XRCT and the dissolution performance, enabling prediction of dissolution performance utilizing non-destructive imaging data. This workflow provides insight into the physical variability of MT populations that are generated during manufacturing, enabling optimization of critical tableting and coating parameters to achieve the target dissolution criteria. Through this mechanistic understanding, quality is built into the final drug product through rational development of formulation and process parameters. [Display omitted] [ABSTRACT FROM AUTHOR]

Attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopic imaging has been used in combination with UV detection to study the release of a model poorly water-soluble drug, indomethacin, when formulated with selected drug carriers. Firstly, formulations of indomethacin and nicotinamide in varying weight ratios were studied since novel tablet dosage forms containing multi-drugs are of industrial interest. The in situ spectroscopic imaging measurements of the dissolving tablets showed that as the loading of indomethacin was increased, the rate of drug release changed from one that expressed first-order drug release to one which showed zero-order drug release. Two drug release mechanisms have been identified from the recorded spectroscopic images and UV dissolution profiles. To further validate these mechanisms, specific formulations containing the model drug and two other excipients, urea and mannitol, were studied. The formulations with urea showed similar first-order release, indicative of the drug-carrier interactions. Whereas, the indomethacin/mannitol formulations showed a zero-order release curve explained by disintegration of the tablet. ATR-FTIR spectroscopic imaging provided highly chemically specific information as well as the spatial distribution of the components during the dissolution process which has demonstrated the potential of this combined analytical setup to determine the mechanisms of drug release. [ABSTRACT FROM AUTHOR]

In this paper, the intrinsic dissolution profiles of naproxen (NAP) at pH values of 1.5 and 3.0 and of trimethoprim (TMP) at pH values of 1.5, 3.0, 5.0, 6.5 and 7.2 were measured. Meanwhile, the dissolution profiles of NAP and TMP from cylindrical tablets were measured at different temperatures (298.15 K, 305.15 K, 301.15 K and 310.15 K) and stirring speeds (50 rpm, 100 rpm and 150 rpm) as well as at different pH values (1.5, 3.0, 5.0, 6.5 and 7.2). Additionally the pH-dependent solubilities of both APIs were measured and modeled. The chemical-potential-gradient model combined with the perturbed-chain statistical associating fluid theory (PC-SAFT) was applied to predict the dissolution profiles of the cylindrical tablets of NAP and TMP under different conditions based on the analysis of their intrinsic dissolution profiles as well as on the determination of the surface-area reduction of the API tablets during dissolution. It was shown that the predicted dissolution profiles of the tablets under different conditions were in a good accordance with the experimental findings. [ABSTRACT FROM AUTHOR]

Abstract: The Discrete Element Method (DEM) was used to generate an unstructured mesh over which mass transfer equations were solved. This has been applied to model swelling and drug release from pharmaceutical tablets and is useful for studying in vitro–in vivo correlation (IVIVC) and virtual formulation development. Parametric studies were conducted into the effect of tablet shape and aspect ratio, polymer properties and shell thickness, and boundary conditions around the tablet on drug release time (t 90), the shape of the release curve and tablet evolution. The first study showed that drug release from tablets containing the same mass of polymer and drug but having different shapes and aspect ratios was only dependent on aspect ratio and not tablet shape. Investigations into polymer properties and coating thickness showed that drug release is fastest for moderately swelling polymers and that similar t 90 can be obtained for different combinations of parameters. The final study into different boundary conditions found that for highly soluble drugs, the polymer was the rate limiting step for drug release but in other cases, release was limited by the low permeability of the boundary. The increase in bulk volume also slowed drug release and demonstrated that both permeability and bulk volume couple to influence drug release. [Copyright &y& Elsevier]

Abstract: This work uses ATR-FTIR spectroscopic imaging to study the dissolution of delayed release and pH resistant compressed coating pharmaceutical tablets. Tablets with an inner core and outer shell were constructed using a custom designed compaction cell. The core of the delayed release tablets consisted of hydroxypropyl methylcellulose (HPMC) and caffeine. The shell consisted of microcrystalline cellulose (MCC) and glucose. The core of the pH resistant formulations was an ibuprofen and PEG melt and the shell was constructed from HPMC and a basic buffer. UV/vis spectroscopy was used to monitor the lag-time of drug release and visible optical video imaging was used as a complementary imaging technique with a larger field of view. Two delayed release mechanisms were established. For tablets with soluble shell sections, lag-time was dependent upon rapid shell dissolution. For tablets with less soluble shells, the lag-time was controlled by the rate of dissolution medium ingress through the shell and the subsequent expansion of the wet HPMC core. The pH resistant formulations prevented crystallization of the ibuprofen in the core during dissolution despite an acidic dissolution medium. FTIR imaging produced important information about the physical and chemical processes occurring at the interface between tablet sections during dissolution. [Copyright &y& Elsevier]

Abstract: A model is presented which can be used to simulate polymer swelling and drug release from tablets using a combination of the Discrete Element Method (DEM) and solving mass transfer over an unstructured grid formed by the DEM elements. This work extends a recently developed single-component swelling and dissolution model by incorporating an extra component (drug) that can be either homogeneously or heterogeneously dispersed within the tablet. Parametric studies were conducted on some of the key parameters which affect drug release, namely the drug distribution, maximum swelling ratio of the polymer and the drug–polymer diffusivity dependence. The drug heterogeneity study showed that burst release (i.e. dose-dumping) increased as drug loading increased since the polymer could not form a gel layer to surround the tablet but the time taken for 99% drug release was not significantly different when compared to the homogeneous case. The maximum swelling ratio study showed that drug release could be limited either by its diffusion through the dense polymer network or the thickness of the gel layer. It was shown that a minimum release time exists where the drug diffusivity and gel layer thickness would give fast drug release. The drug–polymer diffusivity study showed that drug release could become closer to zero-order the more dependent it was on polymer concentration (as the drug would diffuse very slowly until the polymer was very dilute) compared to more Fickian release if the drug''s diffusion coefficient was not as dependent on polymer concentration. Simulated drug release was compared against experiments where tablets containing 10% or 60% w/w nicotinamide and HPMC k100LV were dissolved and imaged using a combination of Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopic imaging and downstream monochromatic UV/Visible detection. The FTIR images and extracted concentration profiles showed that water ingress and drug release were faster for the 60% nicotinamide tablet and that the model could predict drug release using only pure component parameters and the respective mass fractions of drug. [Copyright &y& Elsevier]

ABSTRACT A negative food effect, i.e. a decrease in bioavailability upon the co-administration of compounds together with food, has been attributed particularly with high solubility/low permeability compounds (BCS class III). Different mechanisms have been proposed including intestinal dilution leading to a lower concentration gradient across the intestinal wall as well as binding of the active pharmaceutical ingredient to food components in the intestine and thereby decreasing the fraction of the dose available for absorption. These mechanisms refer primarily to the compound and not to the dosage form. An increase in viscosity of the dissolution fluid will in particular affect the absorption of BCS type III compounds with preferential absorption in the upper small intestine if the API release is delayed from the dosage form. The present study demonstrated that the increase in viscosity of the dissolution medium, following ingestion of a solid meal, may drastically reduce disintegration and dissolution. For that purpose the viscosity of the standard FDA meal was determined and simulated by solutions of HPMC in buffer. As model formulations, three commercially available tablets containing trospium chloride, a BCS class III m-cholinoreceptor antagonist was used. Trospium chloride drug products have been described to undergo a negative food effect of more than 80% following ingestion with food. The tablets showed prolonged disintegration times and reduced dissolution rates in viscous media, which could be attributed to changes in the liquid penetration rates. The effect was particularly significant for film-coated tablets relative to uncoated dosage forms. The results show the necessity of considering media viscosity when designing in vitro models of drug release for BCS type III drug formulations. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The role of poloxamer 188, water and binder addition rate, on retarding dissolution in immediate-release tablets of a model drug from BCS class II was investigated by means of multivariate data analysis (MVDA) combined with design of experiments (DOE). While the DOE analysis yielded important clues into the cause-and-effect relationship between the responses and design factors, multivariate data analysis of the 40+ variables provided additional information on slowdown in tablet dissolution. A steep dependence of both tablet dissolution and disintegration on the poloxamer and less so on other design variables was observed. Poloxamer was found to increase dissolution rates in granules as expected of surfactants in general but retard dissolution in tablets. The unexpected effect of poloxamer in tablets was accompanied by an increase in tablet-disintegration-time-mediated slowdown of tablet dissolution and by a surrogate binding effect of poloxamer at higher concentrations. It was additionally realized through MVDA that poloxamer in tablets either acts as a binder by itself or promotes binder action of the binder povidone resulting in increased intragranular cohesion. Additionally, poloxamer was found to mediate tablet dissolution on stability as well. In contrast to tablet dissolution at release (time zero), poloxamer appeared to increase tablet dissolution in a concentration-dependent manner on accelerated open-dish stability. Substituting polysorbate 80 as an alternate surfactant in place of poloxamer in the formulation was found to stabilize tablet dissolution. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the combined effect of pH modifiers and nucleation inhibitors on enhancing and sustaining the dissolution of AMG 009 tablet via supersaturation. Several bases and polymers were added as pH modifiers and nucleation inhibitors, respectively, to evaluate their impact on the dissolution of AMG 009 tablets. The results indicate that sodium carbonate, among the bases investigated, enhanced AMG 009 dissolution the most. HPMC E5 LV, among the nucleation inhibitors tested, was the most effective in sustaining AMG 009 supersaturation. The release of AMG 009 went from 4% for tablets which did not contain both sodium carbonate and HPMC E5 LV to 70% for the ones that did, resulting in a 17.5-fold increase in the extent of dissolution. The effect of compression force and disintegrant on the dissolution of tablets were also evaluated. The results indicate that compression force had no effect on AMG 009 release. The addition of disintegrating agents, on the other hand, decreased the dissolution of AMG 009. [ABSTRACT FROM AUTHOR]

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier ( e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement. [ABSTRACT FROM AUTHOR]

Abstract: The impact of the addition of a wetting agent, the surfactant sodium lauryl sulfate (SLS), on the tablet hardness of a dry granulated, solid oral dosage form was investigated. In three batches, SLS was added concurrently with: (1) a poorly soluble, highly hydrophobic active pharmaceutical ingredient (API) and the other excipients prior to the initial blending step, (2) magnesium stearate prior to roller compaction, or (3) magnesium stearate prior to tableting. A fourth batch, which did not contain SLS, served as a control. The maximum hardness of 100mg, 1/4″-SRC tablets for the four batches – SLS added initially, prior to roller compaction, prior to tableting, and no SLS – were 61±3, 71±3, 89±5, and 86±3N, respectively, suggesting reduced processing of SLS improves tablet hardness by ∼50%. Dissolution of the tablets in 900ml of simulated gastric fluid with paddles at 75rpm showed that: (1) there was no impact on the insertion point of SLS into the process on API dissolution, and (2) that the presence of SLS improved dissolution by 5% compared to the control tablets. Adding SLS just prior to tableting can improve tablet hardness and yield similar dissolution performance relative to SLS addition prior to the initial blending step. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this work was to develop and validate a method to assess the dissolution behaviour of rociverine sugar-coated tablets. In our laboratories, an HPLC–MS in reverse phase method of analysis was developed for the dosage of unknown rociverine solution. This analytical method was applied to determine the dissolution rate of rociverine tablets produced by the industrial procedure, because there is no official method description. Dissolution tests were carried out in sink conditions as follows: dissolution medium HCl 0.01N, paddle rotation speed 50rpm and vessel volume 1000ml. The dissolution test gave satisfactory results: 95% of the drug was dissolved within 30min and drug dissolution was concluded after 60min. The method was demonstrated to be adequate for Quality Control of rociverine tablets. Validation was inferred from specificity, linearity, precision, accuracy and robustness. [Copyright &y& Elsevier]

Abstract: Compressed mini-tablets systems are presented as a biphasic delivery system designed for zero-order sustained drug release. The outer layer that fills the void spaces between the mini-tablets was formulated to release the drug in a very short time (fast release), while the mini-tablets provided a prolonged release. Different composition (HPMC or EC) and number (10 or 21) of mini-tablets were used to obtain different drug release rates. The in vitro performance of these systems showed the desired biphasic behaviour: the drug contained in the fast releasing phase (powder enrobing the mini-tablets) dissolved within the first 2min, whereas the drug contained in the mini-tablets was released at different rates, depending up on formulation. Based on the release kinetic parameters calculated, it can be concluded that mini-tablets containing HPMC were particularly suitable approaching to zero-order (constant) release over 8h time periods. [Copyright &y& Elsevier]

This study evaluated and optimised the ninhydrin assay as a tool for measuring the in vitro release and dissolution of chitosan from solid dosage forms. The precision and accuracy of the assay for the type of chitosan used in the study were examined by measuring the inter- and intra-sample variation and found to be within acceptable limits. The assay was applied practically to construct a pH/solubility profile for chitosan and subsequently to measure the release and dissolution of chitosan from dosage forms in the presence and absence of a model drug, sodium salicylate. Assay performance was found to be satisfactory over a wide range of physiologically relevant pH values. It is concluded that the ninhydrin assay is an essential aid in the design and testing of solid dosage forms with different chitosan–drug release profiles. [Copyright &y& Elsevier]

A 24−1 fractional factorial design was used to evaluate the effect of various process variables in fluid bed granulation, on the physico-chemical properties of granule and tablet containing a high dose, poorly water soluble, low density, and micronized drug. The process variables studied were inlet air temperature, inlet air flow, spray rate of the binder solution, and atomization air pressure. Tablets with identical composition, weight, size and hardness were also manufactured in a high shear granulator and their physical properties were determined and compared with those produced by the fluidized bed granulation method. Except for the granule size distribution, other physical properties of granulations and tablets produced in a fluid bed granulator are independent of the selected process variables within the study range. Both atomization air pressure and spray rate of the binder solution had strong impact on granule size distribution. Irrespective of the process conditions used in the fluid bed granulation, granules from this process were more porous, less dense and more compressible than the granules from the high shear granulation process. Comparable tablet dissolution rates to those prepared by the optimized high shear granulation method can be achieved by selecting the appropriate process conditions in fluid bed granulation. These results suggest that wet granulation tablets of a high dose, poorly water soluble, low density, micronized drug can be manufactured using a fluidized bed granulation method, with comparable tablet dissolution rates to those produced with an optimized high shear granulation method. [Copyright &y& Elsevier]