Manufacture of slow-release matrix granules by wet granulation with an aqueous dispersion of quaternary poly(meth)acrylates in the fluidized bed

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.     

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.     

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 %.     

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.     

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.     

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.     

Aqueous Film-Coating Vaporization Efficiency

Abstract

A steady-state condition is achieved during most of an aqueous film-coating cycle, i.e., the rate of application of moisture to the tablet bed is equal to its rate of evaporation. A mathematical model was developed for the steady-state condition to describe the efficiency of evaporation of the aqueous solvent for any set of drying conditions (inlet air flow rate, temperature, and humidity) and spray rate of coating suspension. The model was tested utilizing a series of different coating conditions and coating compositions. A vaporization efficiency, E_s, was defined as a means to assess a reproducible coating end point. E_s values for each coating formula fell within a narrow range. The hydroxypropyl cellulose coating system had a significantly lower E_s value due to the higher tackiness that occurs with this polymer during film formation.     

Important Parameters for the Manufacture of Slow-Release Matrix Pellets With an Aqueous Dispersion of Quaternary Poly(meth)acrylates in the Rotary Fluidized Bed

ABSTRACT

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.     

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.     

Effect of Aqueous Film Coating Conditions on Water Removal Efficiency and Physical Properties of Coated Tablet Cores Containing Superdisintegrants

Abstract

Few studies have examined the effect of aqueous film coating process conditions on the physical integrity of the final coated product. Characterization of the aqueous film coating process was previously carried out by selecting water removal efficiency as the response variable to detect and monitor moisture accumulation in the tablet bed [1]. In this study, regression techniques were utilized to obtain the relationship between some physical characteristics of aqueous film coated tablet cores that contained superdisintegrant and several process parameters such as inlet air temperature, spray rate, and pan speed. Tablet response variables measured included residual moisture content, tensile strength and percent porosity. Predicted values of these properties were plotted as a function of the inlet air temperature and the coating solution spray rate. The correlations between the coated tablet response variables and the water removal efficiency of the coating process indicated that coated tablet properties such as residual moisture content, tensile strength, and porosity were linearly correlated with the water removal efficiency of the coating process, which is indicative of the environmental coating conditions present in the coating pan.     

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.     

Aging of Tablets Prepared by Direct Compression of Bases with Different Moisture Content

Abstract

Properties of aged tablets prepared by the wet granulation method were found to be affected by the moisture content of the granules. In this study, the storage-induced changes in hardness, disintegration and drug release were evaluated for tablets made by direct compression of three different bases with different initial moisture content. Tablets with high initial moisture content were found to increase in hardness upon storage. The magnititude of such increase is dependant upon the physical properties of the base and the absolute moisture content. The increase in hardness may increase the disintegration time and decrease drug release. Tablets with low initial moisture content were minimally affected by storage. The gain of moisture by some of these tablets led to enhancement in disintegration and drug release. Among the tablets studied lactose based tablets with different initial moisture content were found to be the most resistant to changes upon storage.     

Carbamazepine Modified Release Dosage Forms

Abstract

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Heat transfer and the combustion temperature of coke particles in a fluidized bed

The temperature of carbon particles undergoing combustion in a fluidized bed is measured. Heat-transfer laws are ascertained.Notation a diffusivity of air - c heat capacity of air - D diffusion coefficient of oxygen in air - d₀, d initial and running diameters of carbon sphere - d_i diameter of inert particles - k rate constant for carbon monoxide combustion - q calorific value of carbon oxidation to CO₂ - T temperature difference between burning particle and fluidized bed - X, X_n oxygen concentration in the fluidized bed and on the surface of the burning particle - Z, Z_n running concentration of carbon monoxide and concentration on the surface of the burning particle - heat-transfer coefficient between fluidized bed and burning particle - _m maximum heat-transfer coefficient between fluidized bed and a stationary body submerged in the bed - masstransfer coefficient between fluidized bed and burning particle - thermal conductivity of air - kinematic viscosity of air - ₀, gr, ₄ density of oxygen, air, and inert material - relative thickness of burning gas layer - relative thickness of diffusion boundary layer Translated from Inzhenerno-Fizicheskii Zhurnal, Vol. 42, No. 1, pp. 21–27, January, 1982.     

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.     

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 %.     

Effect of Various Polymers on Formulation of Controlled Release (CR) Ibuprofen Tablets by Fluid Bed Technique

Abstract

The need for controlled release (CR) formulations of ibuprofen tablet, is well recognized. Some such formulations have been marketed but in general only patented.

The purpose of this study was to develop an air suspension method, using a laboratory scale fluidized bed drier to coat the ibuprofen granules. Different polymers including, Eudragits L100, S100, RL100, RS100, L100+S100 (1:1), RL100+RS100 (1:1), ethyl cellulose (EC) and Eudragit RS100+EC (1:1) were utilized. The drug release medium consisted of buffer pH 1.2 for 1st 2h, buffer pH 4.5 for 2nd 2h and buffer pH 7.5 for remaining period of time in all experiments, but the release behaviour of the drug from some formulations was also studied using distilled water. Of the polymers investigated, Eudragit RS100, EC, Eudragit S100 and Eudragit RS100+EC (1:1) exhibited proper release characteristics when used as coating materials. The release patterns were analyzed from the standpoint of diffusion-controlled processes and as first-order kinetics.     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

Abstract

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly