Manufacture of Slow-Release Matrix Granules by Wet Granulation with an Aqueous Dispersion of Quaternary Poly(meth)acrylates in the Fluidized Bed

ABSTRACT

Slow-release matrix granules were manufactured in the fluidized bed using an aqueous dispersion of quaternary poly(meth)acrylates (Eudragit® RS 30 D) as binder for granulation. A factorial design was carried out to investigate the influence of the following parameters, spraying rate, applied polymer amount, and inlet air temperature, on various granule properties. Prerequisites for a slow release of the model drug theophylline are high spraying rate, high amount of polymer, and low inlet air temperature. No considerable decrease of the drug release rate can be achieved without a subsequent curing of the dry granules. A clear correlation exists between the moisture content of the fluidized bed, indicated by the terminal moisture content (TMC), and the mean dissolution time for 80% of the drug (MDT₈₀).     

Proportional control of moisture content of granules by adjusting inlet air temperature in fluidized bed granulation using near-infrared spectroscopy

For process control of fluidized bed granulation process, we investigated proportional (P) moisture content control via adjustment of inlet air temperature in proportion to the difference between measured and target moisture content of granules. Here, we first validated P moisture content control by comparison with bed temperature control. We then confirmed that P moisture content control is effective in maintaining the moisture content, and in minimizing the variance of the particle size of granules following granulation. Furthermore, we observed that when the target temperature was higher than the measured value of inlet air temperature the P moisture content control response was accelerated. In contrast, when the target temperature was less than the measured value of inlet air temperature (<50 °C) the response was delayed. In summary, P moisture content control has good scalability and can be introduced without changing granulation conditions in the development of orally administered pharmaceutical products.     

Use of experimental designs to optimize fluidized bed granulation of maltodextrin

The goal of this study was to use the experimental design approach in order to determine which process parameters are the most influent to granules properties. The agglomeration process was performed with a fluidized bed processor equipped with a top-spray tilted nozzle. The granules were obtained by binding fluidized particles of maltodextrin (DE 12) with an aqueous solution of maltodextrin. The variables considered in the experimental design were fluidization air flow rate, drying air temperature, spraying pressure and binder flow rate. The physical properties of the granules were evaluated in terms of granule size, particle size distribution, dissolution time and flowability. Moreover, the amount of binder for each experiment was noted. The statistical analysis performed with Statgraphics® Centurion version XVI software indicated that the best operating conditions were found for low fluidization air flow rate, high drying air temperature, high spraying pressure and high binder flow rate. The study also revealed the difficult task of acquiring all the optimum properties at the same time.     

Regulating Drug Release Via Non-Uniform Distribution of Coating Composition in Multilayer Drug-Coated Granules

Multilayer drug-coated granules with a non-uniform distribution of the coating composition specifically the drug loading and the polymer viscosity, across the thickness of the film matrix were prepared by the fluidized bed coating process. The rate and duration of diphenhydramine hydrochloride release from the coated granules can be modified through control of the gradient change in the coating composition across the thickness of the methylcellulose (MC) film matrix. A steeper gradient change across the film matrix resulted in a slower overall release rate. Formulations with gradient drug loading distribution exhibited an extended release time that can be twice as long as that for the control formulation. Gradient layered matrices obtained by sequentially depositing different viscosity grades of MC produced release profiles that differed from film matrices prepared using MC blends.     

Regulating Drug Release Via Non-Uniform Distribution of Coating Composition in Multilayer Drug-Coated Granules

Multilayer drug-coated granules with a non-uniform distribution of the coating composition specifically the drug loading and the polymer viscosity, across the thickness of the film matrix were prepared by the fluidized bed coating process. The rate and duration of diphenhydramine hydrochloride release from the coated granules can be modified through control of the gradient change in the coating composition across the thickness of the methylcellulose (MC) film matrix. A steeper gradient change across the film matrix resulted in a slower overall release rate. Formulations with gradient drug loading distribution exhibited an extended release time that can be twice as long as that for the control formulation. Gradient layered matrices obtained by sequentially depositing different viscosity grades of MC produced release profiles that differed from film matrices prepared using MC blends.     

Characteristics of piroxicam granules prepared by fluidized bed hot melt granulation

The aim of this study was to investigate the granulation of piroxicam by fluidized bed hot melt method using polyethylene glycol 4000 as the hydrophilic carrier and spray dried lactose as the fluidizing substrate. The effects of the spray nozzle air flow rate, axial position of the spray nozzle and load of fluidizing substrate on granules properties were investigated using a Box Behnken factorial design. The dependent variables evaluated were the mean particle size distribution, drug content and flow properties of the granules. The granule sizes ranged from 453.5?µm to 894.7?µm and piroxicam content was above 83.2%. However, the response surface ANOVA showed that sizes and piroxicam content were not affected by the granulation conditions and microscopy evidenced the presence of piroxicam crystals on granules surface. On the other hand, ANOVA showed that the granules flow properties were affected at the significance level of 5%. Thermal and infrared analysis showed that there was no interaction of piroxicam with carriers during the process. The dissolution profile of piroxicam was remarkably improved. Therefore, the results confirm the high potential of the fluidized bed hot melt granulation technique to obtain granules with enhanced drug solubility and release rates.     

Preparation of codeine-resinate and chlorpheniramine-resinate sustained-release suspension and its pharmacokinetic evaluation in beagle dogs

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS).

Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE® IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8-12 g/min, the inlet air temperature was 50-60°C, the outlet air temperature was 32-38°C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeratation of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content.

In the present study, the rates of drug release from both drug resinate beads were measured in 0.05M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chloropheneramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05M KCl solution for codeine and 0.5M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance.

Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of T_max and the lower value of C_max, which meant an obviously sustained release effect, and its relative bioavailability of codeine and chlorpheniramine were (103.6 ± 14.6)% and (98.1 ± 10.3)%, respectively, compared with the reference preparation. These findings indicated that a novel liquid sustained release suspension made by using IERs as carriers and subsequent fluidized bed coating might provide a constant plasma level of the active pharmaceutical ingredient being highly beneficial for various therapeutic reasons.     

The miniwid-coater: I. design and evaluation of a temperature-controlled miniature fluid-bed pan coater

A novel miniature laboratory-scale pan coater has been developed. Small batches of 50 to 100 g of pellets, granules, large crystalls and small tablets allow the formulation development with minimal quantities of valuable drugs and new active ingredients. Although originally it is a pan coater, the core bed will be slightly fluidized by the inlet air flow due to the small dimensions of the coating pan. This allows a rapid drying and the loss of coating materials will be negligible.

A computer was used to control the core bed temperature during the coating process by varying the spraying rate of an analytical dosing pump. Additionally, the drying air temperature can be adopted. It was possible to change the parameters during the process to optimize the operation conditions within one run. The computer program described in this article provides a constant bed temperature with a precision of ± 0.3 °C.

In the MiniWiD-Coater, neutral pellets have been loaded with bisacodyl and then enteric-coated with aqueous dispersions of Eudragit L 30 D. Batch homogeneity and reproducibility were excellent. Friability of the cores and abrasion of the coat remained low. The loss of coating material during operation was always below 5 %.     

Controlled-release behavior of diphenhydramine hydrochloride loaded neutral microgranules and coated using ethylcellulose water dispersion

The development of a loading method of a water-soluble drug using aqueous binding solution to produce microgranules that were then coated with an aqueous ethylcellulose dispersion to sustain drug release is described. The results, in terms of drug used, showed that besides the fluidized bed parameters, the amount of drug dissolved in the binder solution plays an important role in obtaining a satisfying result during the spraying process. Thus, it seems necessary to determine the critical concentration above which the material started to adhere to the interior of the fluidization column, and the possibility of drug layering onto carrier material is aggravated. ANOVA of the time parameter for release of 63.2% of total drug (td) value showed significant influence of ethylcellulose (Aquacoat ECD-30) and dibutyl sebacate concentration on diphenhydramine hydrochloride (DPH) release. The dissolution rate decreased with an increase in polymer concentration. The diffusional exponent n of the Peppas equation indicated that the DPH release kinetic was non-Fickian but approached Fickian diffusion, particularly at higher coating levels.     

In vitro dissolution studies of sodium diclofenac granules coated with Eudragit L-30D-55 by fluidized-bed system

The objective of this work was to study the dissolution process of sodium diclofenac granules coated with a polymeric suspension of Eudragit L-30D-55® by fluidized bed. Methacrylic acid-methylmetacrylate copolymer, also known as Eudragit, has been used as a pH sensitive coating material to protect drug substances prior to delivery to the human intestines. The sodium diclofenac granules were prepared by wet granulation technology using microcrystalline cellulose (MICROCEL), sodium diclofenac, and polivinilpirrolidone K-30. The granules coating operation was carried out in a fluidized bed with top spraying by a double-fluid nozzle. The dissolutions studies of the coated granules were performed in triplicate in a dissolution test station according to USP XXIII (1995) “in vitro testing requirements” Method A (paddle method, rotation of 100 RPM and temperature fixed at 37°C). The dissolution mediums were 0.1N HCl solution and a pH 6.8 phosphate buffer solution, following the pH change dissolution procedure specified in USP for enteric-coated articles: 2 h of exposure to 750 mL of 0.1N HCl followed by testing in 1000 mL of pH 6.8 phosphate buffer, the pH being adjusted with 250 mL of 0.2 M tribasic sodium phosphate solution. The released amount of sodium diclofenac was periodically determined by UV spectrophotometry at wavelength of 276 nm, using a spectrophotometer UV-VIS HP 8453. The coated product showed gastric resistance properties confirming the feasibility of the fluidized bed for applying enteric coating in granules and pharmaceutical powders.     

The miniwid-coater: I. design and evaluation of a temperature-controlled miniature fluid-bed pan coater

Abstract

A novel miniature laboratory-scale pan coater has been developed. Small batches of 50 to 100 g of pellets, granules, large crystalls and small tablets allow the formulation development with minimal quantities of valuable drugs and new active ingredients. Although originally it is a pan coater, the core bed will be slightly fluidized by the inlet air flow due to the small dimensions of the coating pan. This allows a rapid drying and the loss of coating materials will be negligible.

A computer was used to control the core bed temperature during the coating process by varying the spraying rate of an analytical dosing pump. Additionally, the drying air temperature can be adopted. It was possible to change the parameters during the process to optimize the operation conditions within one run. The computer program described in this article provides a constant bed temperature with a precision of ± 0.3 °C.

In the MiniWiD-Coater, neutral pellets have been loaded with bisacodyl and then enteric-coated with aqueous dispersions of Eudragit L 30 D. Batch homogeneity and reproducibility were excellent. Friability of the cores and abrasion of the coat remained low. The loss of coating material during operation was always below 5 %.     

A protein powder agglomeration process using açaí pulp as the binder: An analysis of the process parameters

This work investigated the fluidized bed agglomeration of a plant protein powder blend using an açaí pulp binder in order to improve the physical and handling properties. The blend was prepared mixing isolated pea protein powder and concentrated rice protein powder. The influence of air temperature and binder flow rate on the moisture content, particle size and process yield was evaluated using a factorial design. The anthocyanins content, wettability and flowability of the powder was also evaluated. The agglomeration produced large granules with better physical properties, indicating that açaí pulp can be used as a binder. Statistical analysis showed that binder flow rate had the greatest influence on moisture content and process yield; air temperature had a greater effect on particle size. The optimum condition (T = 75 °C, Q = 2.0 mL/min) resulted in granules that were twice as large as the initial particles. Anthocyanins were incorporated (2.34 mg/100 g) with an acceptable moisture content (≤10%) and a high yield (>75%). Flowability was greater in the agglomerated powder than in the raw material with a wetting time reduction of about 77.0%. The resulting protein powder combines the properties of an instant powder with health and nutritional benefits.     

Melt granulation in fluidized bed: a comparative study of spray-on versus in situ procedure

Objective: The aim of this study was to investigate the influence of process parameters, binder content and binder addition method on characteristics of the granules obtained by melt granulation (MG) in fluidized bed.

Methods: Spray-on experiments were performed according to 2³ full factorial design. The effect of binder content, molten binder feed rate, and spray air pressure on granule size and size distribution, granule shape, ?owability and drug release rate was investigated. In the in situ experiments, the influence of binder particle size and binder content was evaluated. Solid-state characterization was performed by means of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy.

Results: Size of the granules obtained by spray-on procedure was significantly influenced by binder content and spray air pressure, while the width of particle size distribution was mainly affected by binder feed rate. Spray air pressure showed the most significant influence on granule shape. It was shown that smooth and spherical particles with good flow properties may be obtained by both procedures, spray-on and in situ MG. The results obtained indicated the influence of agglomeration mechanism on granule sphericity, with higher degree of granule sphericity observed when immersion and layering was the dominant mechanism. Paracetamol release from granulates was very rapid, but after compression of the granules into tablets, drug release was considerably slower. Solid-state analysis confirmed that the physical form of the granulate components remained unaffected after the MG process.

Conclusion: The results presented indicate that MG in fluidized bed could be a good alternative to conventional granulation techniques.     

In Vitro Dissolution Studies of Sodium Diclofenac Granules Coated with Eudragit L-30D-55® by Fluidized-Bed System

Abstract

The objective of this work was to study the dissolution process of sodium diclofenac granules coated with a polymeric suspension of Eudragit L-30D-55® by fluidized bed. Methacrylic acid-methylmetacrylate copolymer, also known as Eudragit, has been used as a pH sensitive coating material to protect drug substances prior to delivery to the human intestines. The sodium diclofenac granules were prepared by wet granulation technology using microcrystalline cellulose (MICROCEL), sodium diclofenac, and polivinilpirrolidone K-30. The granules coating operation was carried out in a fluidized bed with top spraying by a double-fluid nozzle. The dissolutions studies of the coated granules were performed in triplicate in a dissolution test station according to “in vitro testing requirements” Method A (paddle method, rotation of 100 RPM and temperature fixed at 37°C). The dissolution mediums were 0.1N HCl solution and a pH 6.8 phosphate buffer solution, following the pH change dissolution procedure specified in USP for enteric-coated articles: 2 h of exposure to 750 mL of 0.1N HCl followed by testing in 1000 mL of pH 6.8 phosphate buffer, the pH being adjusted with 250 mL of 0.2 M tribasic sodium phosphate solution. The released amount of sodium diclofenac was periodically determined by UV spectrophotometry at wavelength of 276 nm, using a spectrophotometer UV-VIS HP 8453. The coated product showed gastric resistance properties confirming the feasibility of the fluidized bed for applying enteric coating in granules and pharmaceutical powders.     

Preparation of Codeine-Resinate and Chlorpheniramine-Resinate Sustained-Release Suspension and its Pharmacokinetic Evaluation in Beagle Dogs

ABSTRACT

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS).

Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE® IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8–12 g/min, the inlet air temperature was 50–60°C, the outlet air temperature was 32–38°C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeratation of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content.

In the present study, the rates of drug release from both drug resinate beads were measured in 0.05M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chloropheneramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05M KCl solution for codeine and 0.5M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance.

Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of T_max and the lower value of C_max, which meant an obviously sustained release effect, and its relative bioavailability of codeine and chlorpheniramine were (103.6 ± 14.6)% and (98.1 ± 10.3)%, respectively, compared with the reference preparation. These findings indicated that a novel liquid sustained release suspension made by using IERs as carriers and subsequent fluidized bed coating might provide a constant plasma level of the active pharmaceutical ingredient being highly beneficial for various therapeutic reasons.     

Polymorphic Changes of Thiamine Hydrochloride During Granulation and Tableting

Thiamine hydrochloride was granulated using an instrumented fluidized bed granulator (Hüttlin HKC 05-TJ). Granules consisting of pure thiamine hydrochloride were produced using an aqueous solution of thiamine hydrochloride as the granulating liquid. The effects of process variables such as inlet air temperature, spray rate, and amount of granulating liquid on granule properties are described. Particle size distributions of granules depended mainly on the amount of granulating liquid sprayed into the powder bed. Granules were tableted on a rotary tablet press at four different compression forces. Crushing strengths and disintegration times of all tablets were found to be very low after manufacture, but increased considerably after 4 months of storage at room temperature. Granular materials showed “caking” under the same storage conditions. These changes could be attributed to alterations of the polymorphic form of thiamine hydrochloride. The water-free form, being present directly after granulation, absorbs humidity very fast and is transformed into the monohydrate, which is stable at room temperature. Loss of water takes place during the drying phase of the granulation process and on storage of the substance at temperatures of 50°C and 80°C. During storage at room temperature while exposed to humidity, a transformation into the hemihydrate was observed. This polymorph is transformed during thermal analysis at about 190°C to a water-free form that is stable at higher temperatures.     

Polymorphic changes of thiamine hydrochloride during granulation and tableting

Thiamine hydrochloride was granulated using an instrumented fluidized bed granulator (Hüttlin HKC 05-TJ). Granules consisting of pure thiamine hydrochloride were produced using an aqueous solution of thiamine hydrochloride as the granulating liquid. The effects of process variables such as inlet air temperature, spray rate, and amount of granulating liquid on granule properties are described. Particle size distributions of granules depended mainly on the amount of granulating liquid sprayed into the powder bed. Granules were tableted on a rotary tablet press at four different compression forces. Crushing strengths and disintegration times of all tablets were found to be very low after manufacture, but increased considerably after 4 months of storage at room temperature. Granular materials showed "caking" under the same storage conditions. These changes could be attributed to alterations of the polymorphic form of thiamine hydrochloride. The water-free form, being present directly after granulation, absorbs humidity very fast and is transformed into the monohydrate, which is stable at room temperature. Loss of water takes place during the drying phase of the granulation process and on storage of the substance at temperatures of 50 degrees C and 80 degrees C. During storage at room temperature while exposed to humidity, a transformation into the hemihydrate was observed. This polymorph is transformed during thermal analysis at about 190 degrees C to a water-free form that is stable at higher temperatures.     

Role of continuous moisture profile monitoring by inline NIR spectroscopy during fluid bed granulation of an Enalapril formulation

Background: Granulation and tableting are closely related process steps in the supply chain of pharmaceutical products. Even today, these steps are still optimized independently by trial and error. On the framework of a process analytical technology approach, these processes were evaluated in an integrated approach. Enalapril maleate is a low-dose drug substance with poor granulating and tableting behavior. In order to verify how granulation influences tableting properties, different granulation experiments were performed. Methods: Granulation experiments with fast spraying rate and fast drying as well as fast spraying rate and slow drying, and also combinations of both were run. The obtained granules were then promptly compressed into tablets in a rotary press and subjected to hardness testing. The progress of spraying and drying was controlled by a continuous near-infrared spectroscopic measuring setup. This study confirms that the tablet characteristics. Result/Conclusion: after compression of the granules in comparison to placebo granules are dependent not only on the residual moisture content of the granules but also on the moisture profiles during the entire fluid bed granulation process.     

Drug Release and Surface Morphology Studies on Salbutamol Controlled Release Pellets

The air suspension technique was employed to prepare controlled release pellets of Salbutamol (as the sulphate). The aim of the present study was to determine the influence of various film coating additives on the release characteristics and surface morphology features of salbutamol sulphate pellets coated with Eudragit^R RS30D which is the aqueous dispersion of a polymer synthesised from acrylic and methacrylic acid esters. Surface morphology features, which were examined using Scanning Electron Microscopy, revealed that triethyl citrate (plasticiser) was essential for the coalescence of polymeric membranes around the drug-loaded spheres. Higher concentrations (12.5%) of triethyl citrate displayed a more uniform and continuous polymer film resulting in a slower in vitro drug release. Micrographs of the cross-sections of pellets with higher concentrations of Eudragit^R RS30D indicated the formation of thicker polymer membranes which accounted for the slower drug release rates. Hydroxypropyl methylcellulose (HPMC) inclusion in the polymer film coating increased salbutamol release rates due to its hydrophilic nature which promoted the formation of pores and cracks on the polymer films. A slower in vitro release of salbutamol was observed with higher concentrations of the hydrophobic anti-tackiness agent, magnesium stearate. The addition of salbutamol sulphate powder to the polymer dispersion enhanced drug release rates due to increased film permeability. Polyethylene glycol 200 (PEG 200) resulted in an increased in vitro drug release due to both its water soluble nature as well as impairment of film formation attributed to too high a plasticiser content in the coating formulation. As compared to polyethylene glycol 300 (PEG 300) as a plasticiser, triethyl citrate retarded drug release to a greater extent and formed more homogeneous and compact polymer films. The moisture content of PEG 300 plasticised pellets showed a 0.6% increase in moisture content while triethyl citrate plasticised pellets displayed a loss of 0.01% moisture 8 weeks after storage at room temperature.     

Important parameters for the manufacture of slow-release matrix pellets with an aqueous dispersion of quaternary poly(meth)acrylates in the rotary fluidized bed

The manufacture of slow-release matrix pellets with an aqueous dispersion of quaternary poly(meth)acrylates was investigated in the rotary fluidized bed. By considering the moisture content of the fluidized bed to be the key process parameter, it was measured on-line throughout the whole manufacturing process. A specially designed sampling device opened new ways to apply NIR spectrometry in laboratory scale processes. It was shown that reproducibly improved pellet properties can be achieved by reproducing the moisture content of the (rotary) fluidized bed. Moisture plateaus proved to be a suitable way to optimize the sphericity of the pellets. Premoisturizing was found to be a very effective tool to achieve slow-release dissolution of the model drug theophylline.