Investigations on Compaction Behavior of Kollidon®SR-Based Multi-component Directly Compressed Tablets for Preparation of Controlled Release Diclofenac Sodium.

The physics of tablets mixtures has gained much attention lately. The purpose of this work is to evaluate the compaction properties of Kollidon® SR (KSR) in the presence of different excipients such as Microcrystalline cellulose (MCC), Monohydrous lactose (MH Lactose), Poly (vinyl acetate) (PVA100), and a water-soluble drug Diclofenac sodium (DNa) to prepare once daily formulation. Tablets were prepared using direct compression and were compressed into flat-faced tablets using hydraulic press at various pressures. The combination of MCC and KSR in the tablets showed reduced porosity, and almost constant low Py values as KSR levels increased; also, KSR-DNa tablets had higher percentage porosity and crushing strength values than KSR-MH Lactose tablets. The crushing strengths of KSR-MCC tablets were larger than those of KSR-DNa tablets. Ternary mixture tablets comprised of KSR-MCC-DNa showed decreased porosities and low Py values as the percentage of KSR increased especially at high compression pressures but had higher crushing strengths compared to KSR-DNa or MCC-DNa binary tablets. KSR-MH Lactose-DNa ternary tablets experienced lower porosities and crushing strengths compared to KSR-MCC-DNa tablets. Quaternary tablets of KSR-PVA100-MCC-DNa showed lower porosity and Py values than quaternary tablets obtained using similar proportion of MH Lactose instead of MCC. In conclusion, optimum quaternary tablets were obtained with optimum crushing strengths, relatively low Py, and moderate percentage porosities among all prepared quaternary tablets. The drug release of the optimum quaternary tablets demonstrated similar in vitro release profile compared to that of the marketed product with a mechanism of release that follows Korsmeyer-Peppas model.

Investigating the Correlation Between Drug Physical Properties and Physical Characteristics and Drug Entrapment Efficiencies of Chitosan-TPP Nanoparticles.

Chitosan nanoparticles (NPs) have been the subject of intensive research. This study aimed to determine how different drug characteristics such as molecular weights, drug solubility in the processing medium, and drug ionization/charge state affected chitosan NPs particularly their percentage entrapment efficiency (% EE) and mean hydrodynamic diameters (MHDs). Drugs with varying molecular weights but of similar aqueous solubilities were chosen and were dissolved in a 2% chitosan-acetic acid solution. Chitosan NPs were formed using by ionic gelation technique using sodium tripolyphosphate (TPP) at specific concentration and volume ratios of chitosan to TPP. NPs containing Enalapril and Paracetamol displayed better short-term stability in terms of MHDs. A direct relationship between MHDs of NPs and chitosan concentrations was found. In comparison, at both low and high admixed drug concentrations and at high chitosan concentration, larger NPs sizes were associated with the lower molecular weight drug (Paracetamol). However, the study did not demonstrate a direct relationship between NPs characteristics such as MHDs and drugs molecular weights. The ZP of Paracetamol-loaded NPs was lowest at high drug concentrations at all chitosan concentrations compared to other drugs-loaded NPs. When compared to drugs with high and low molecular weights, medium molecular weight Atenolol showed the highest % EE. This clearly indicated that there was no direct correlation between drug molecular weight and % EE, but rather other factors influenced on % EE. Nevertheless, an inverse linear relationship with high correlation coefficients was only found when % EE was plotted against each drug molecular weight divided by the ratio of drugs solubilities in acetic acid to their employed concentrations, however the correlation was inconsistent between drugs of varying molecular weights.

The Influence of Drugs Solubilities and Chitosan-TPP Formulation Parameters on the Mean Hydrodynamic Diameters and Drugs Entrapment Efficiencies into Chitosan-TPP Nanoparticles.

Chitosan is a natural, biocompatible polymer. The aim of this work was to study the influence of drug solubility in 2% v/v acetic acid, formulation parameters, on mean hydrodynamic (MHD) diameters and drug entrapment efficiencies (% EE) into chitosan-TPP nanoparticles (NPs). Drugs of different aqueous solubilities with nearly similar molecular weights were chosen and admixed at several concentrations in 2% acetic acid at different chitosan concentrations and at fixed chitosan to TPP concentrations/volumes ratios. The NPs were freeze-dried, and the supernatants were utilized to determine % EE. Theophylline- and antipyrine-loaded NPs showed the best short-term physical stability in terms of MHD diameters. Antipyrine-loaded NPs possessed the larger MHD diameters, while vitamin C-loaded NPs showed the smallest ones. The relationships between the ratio of drug concentration relative to their solubilities in acetic acid were almost linear for antipyrine and vitamin C-loaded NPs when plotted against and the MHD diameters of NPs, and linear for antipyrine- and theophylline-loaded NPs when plotted against % EE with antipyrine NPs possessing the highest % EE. However, vitamin C- and propylthiouracil-loaded NPs exhibited curvilinear patterns with comparatively lower % EE. The concentration of chitosan, drug solubility in dispersion medium, and the ratio of the concentration of admixed drug relative to its solubility in dispersion medium were found critical in determining % EE and MHD diameters of NPs. It was evident that drugs with extremely low or high solubilities in dispersion medium resulted in low % EE when admixed at both low and high concentrations.

Assessment of Once Daily Controlled-release Ibuprofen Matrix Tablets Prepared using Eudragit ®E100/Carbopol® 971P NF Polymers and their Salt Combinations.

INTRODUCTION: Hydrophilic polymers that swell or dissolve in aqueous media can have the potential to prepare controlled/sustained dosage forms for weakly acidic and poorly soluble drugs. OBJECTIVE: The main objective of this study is to utilize Eudragit®E100 (EE) and Carbopol®971P NF (Cp) polymers and their salt forms for the preparation of a once-daily controlled-release matrix tablet for model drug, Ibuprofen (IB). METHODS: Combinations of the polymers in their base forms (EE)/(Cp) or in their salt forms (EEHCl/ CpNa) were compressed with (IB) into single layer matrix tablets, or otherwise into bilayer tablets. Dissolution profiles were constructed using three different consecutive stages (pH 1.2, 4.8 and 6.8). RESULTS: It was found that the incorporation of (EEHCl) modified the release rates of (IB) from (Cp) based matrix tablets. However, a major enhancement of (IB) release rates occurred when the polymers were combined in their salt forms in a 1:1 ratio by weight. In addition, a bilayer tablet was prepared wherein a relatively rapidly disintegrating layer composed of polymers salts (EEHCl and CpNa), and a second layer containing only (Cp) polymer in its base form in a 1:2 weight ratio possessed excellent release properties and mechanical strength. CONCLUSION: It was concluded that the prepared bilayer tablet could be promising for controlling the release rates of (IB) in an extended manner to allow once-daily administration with an improved pH-independent release behavior.

Preparation and Evaluation of Ternary Polymeric Blends for Controlled Release Matrices Containing Weakly Basic Model Drug.

OBJECTIVE: The objective of this study was to evaluate the suitability of a ternary mixture of smart polymers comprised of Eudragit®E100, Eudragit®L100, and sodium alginate to serve as a carrier for sustained drug release for weakly basic drugs. The model drug chosen in this part of the study is Metronidazole. METHODS: Matrix tablet formulations were prepared by either direct compression or by wet granulation. Dissolution studies were conducted using USP XXΠ rotating paddle apparatus in three different consecutive stages (pH 1.2, 4.8, and 6.8). Tablets made of low to intermediate proportions of sodium alginate and approximately equal proportions of Eudragit®E100 and Eudragit®L100 were found to have a significant modification of drug release rates. RESULTS: Thus, indicating a potential for controlling the drug release for 12 hours depending on polymers ratios in the formulation. The ratio of sodium alginate to total Eudragit® polymers and the ratio of Eudragit®E100 to Eudragit®L100 within the ternary polymeric composition were found critical in determining the controlled release performance. CONCLUSION: Results of swelling studies were in agreement with the dissolution behaviors of the tablets. The findings suggest the significance of the ternary polymeric compositions in controlling the release of a weakly basic drug, Metronidazole.

Withdrawn: Novel Ternary Polymeric Blends for Controlled Release Matrices Containing Weakly Basic Model Drug.

Ahead of Print article withdrawn by publisher.

Development of a Mini-Freeze Dryer for Material-Sparing Laboratory Processing with Representative Product Temperature History.

The goal of the work described in this publication was to evaluate a new, small, material-sparing freeze dryer, denoted as the "mini-freeze dryer or mini-FD", capable of reproducing the product temperature history of larger freeze dryers, thereby facilitating scale-up. The mini-FD wall temperatures can be controlled to mimic loading procedures and dryer process characteristics of larger dryers. The mini-FD is equipped with a tunable diode laser absorption spectroscopy (TDLAS) water vapor mass flow monitor and with other advanced process analytical technology (PAT) sensors. Drying experiments were performed to demonstrate scalability to larger freeze dryers, including the determination of vial heat transfer coefficients, K v . Product temperature histories during K v runs were evaluated and compared with those obtained with a commercial laboratory-scale freeze dryer (LyoStar II) for sucrose and mannitol product formulations. When the mini-FD wall temperature was set at the LyoStar II band temperature (- 20°C) to mimic lab dryer edge vials, edge vial drying in the mini-FD possessed an average K v within 5% of those obtained during drying in the LyoStar II. When the wall temperature of the mini-FD was set equal to the central vial product temperature, edge vials behaved as center vials, possessing a K v value within 5% of those measured in the LyoStar II. During both K v runs and complete product freeze drying runs, the temperature-time profiles for the average edge vials and central vial in the mini-FD agreed well with the average edge and average central vials of the LyoStar II.

Novel Salted Anionic-Cationic Polymethacrylate Polymer Blends for Sustained Release of Acidic and Basic Drugs.

BACKGROUND: Since a unique matrix tablet formulation that independently controls the release of various drug types is in a great demand, the objective of this research was to develop a sustained release matrix tablet as a universal dosage form using a binary mixture of the salt forms of Eudragit polymers rather than their interpolyelectrolyte complexes. METHODS: Tablets were prepared by wet granulation and compressed at different compression forces, depending on drug type. Dissolution tests were conducted using USP XXII rotating paddle apparatus at 50 rpm at 37°C in consecutive pH stages. RESULTS: Tablets containing Ibuprofen (IB) as a model acidic drug and Metronidazole (MD) as a model basic drug showed controlled/sustained release behavior. For IB tablets containing 80% Ibuprofen and 5% (w/w) polymeric combination; the time for 50% of the drug release was about 24 hours compared to 8.5 hours for plain tablets containing 80% IB. In case of MD, the drug release extended to about 7 hours for tablets containing 80% MD and 5% (w/w) polymeric combination, compared to about 1 hour for plain tablets containing 80% MD. In terms of extending the release of medications, the dissolution profiles of the tablets containing polymeric salts forms were found to be statistically superior to tablets prepared by direct compression of the polymers in their powdered base forms, and superior to tablets containing the same polymers granulated using isopropyl alcohol. CONCLUSION: The findings indicated the significance of combining the polymers in their salt forms in controlling the release of various drug types from matrices.

Evaluation of Matrix Tablets Based on Eudragit®E100/Carbopol®971P Combinations for Controlled Release and Improved Compaction Properties of Water Soluble Model Drug Paracetamol.

The purpose of this work was to investigate the influence of Eudragit®E100 polymer in modifying the release rates and compaction properties of water soluble model drug paracetamol from Carbopol®971P NF polymer matrix tablets prepared by direct compression. The effects of the ratio of the two polymers, the total polymeric content, and the tablets mechanical strength on paracetamol release rates were investigated. Dissolution studies were conducted using USP XX Π rotating paddle apparatus at 50 rpm and 37°C at three different stages (pH 1.2, 4.8, and 6.8). Results showed that the polymers combination improved significantly the compaction properties of paracetamol tablets as evident by the higher crushing strengths (8.3 ± 0.4 Kp) compared to polymer-free tablets (3.4 ± 0.2 Kp) at intermediate compression pressure of 490 MPa. When combined with Carbopol®971P NF, Eudragit®E100 was found to be capable of extending paracetamol release for more than 12 h compared to 1 h for polymers-free tablets. The combined polymers were able to control paracetamol release in a pH independent pattern. The f2 (similarity factor) analysis showed that the ratio between the polymers and the total polymer concentration exhibited significant impact on drug release rates. In conclusion, Eudragit®E100 when combined with Carbopol®971P NF was capable of improving the compaction and sustained release properties of paracetamol. Korsmeyer-Peppas model was found to be the most suitable for fitting drug release data. The polymer combinations can potentially be used to control the release rates of highly water soluble drugs.

The dissolution enhancement of piroxicam in its physical mixtures and solid dispersion formulations using gluconolactone and glucosamine hydrochloride as potential carriers.

The solid dispersion technique is one of the most effective methods for improving the dissolution rate of poorly water-soluble drugs; however this is reliant on a suitable carrier and solvent being selected. The work presented explores amino sugars (d-glucosamine HCl and d-gluconolactone) as potential hydrophilic carriers to improve dissolution rate of a poorly water-soluble drug, piroxicam, from physical mixtures and solid dispersion formulations. Solid dispersions of the drug and carrier were prepared using different ratios by the conventional solvent evaporation method. Acetone was used as solvent in the preparation of solid dispersions. Physical mixtures of piroxicam and carrier were also prepared for comparison. The properties of all solid dispersions and physical mixtures were studied using a dissolution tester, Fourier transform infrared, XRD, SEM and differential scanning calorimetry. These results showed that the presence of glucosamine or gluconolactone can increase dissolution rate of piroxicam compared to pure piroxicam. Glucosamine or Gluconolactone could be used as carrier in solid dispersion formulations and physical mixtures to enhance the dissolution rate. Solid state studies showed that no significant changes occurred for piroxicam in physical mixtures and solid dispersion.

Evaluation of tadalafil nanosuspensions and their PEG solid dispersion matrices for enhancing its dissolution properties.

The aim of this work was to prepare and evaluate Tadalafil nanosuspensions and their PEG 4000 solid dispersion matrices to enhance its dissolution rate. Nanosuspensions were prepared by precipitation/ultrasonication technique at 5°C where different stabilizers were screened for stabilization. Nanosuspensions were characterized in terms of particle size and charge. Screening process limited suitable stabilizers into structurally related surfactants composed of a mixture of Tween80 and Span80 at 1:1 ratio (in percent, weight/volume) in adjusted alkaline pH (named TDTSp-OH). The surfactant mixture aided the production of nanosuspensions with an average particle size of 193 ± 8 nm and with short-term stability sufficient for further processing. Solid dispersion matrices made of dried Tadalafil nanosuspensions or dried Tadalafil raw powder suspensions and PEG 4000 as a carrier were prepared by direct compression. Drying was performed via dry heat or via freeze dry. Drug release studies showed that, in general, tablet formulations made of freeze-dried product exhibited faster initial release rates than the corresponding tablets made of oven-dried products which could be attributed to possible larger crystal growth and larger crushing strengths of oven-dried formulations. At best, 60% of drug was released from solid dispersion matrices, while more than 90% of drug was released from TDTSp-OH nanosuspension within the first 5 min. In conclusion, Tadalafil nanosuspensions obtained using a mixed surfactant system provided rapid dissolution rates of Tadalafil that can theoretically enhance its bioavailability.

Evaluation of hydrophilic matrix tablets based on Carbopol(®) 971P and low-viscosity sodium alginate for pH-independent controlled drug release.

BACKGROUND: The aim of this study was to evaluate matrix tablets containing different ratios of Carbopol(®) 971P (CP) to low-viscosity sodium alginate (SA) and assess their suitability for pH-independent controlled drug release. METHODS: Two processing methods (physical mixing, PM and spray-drying, SD) were applied before compaction and the release from corresponding matrices was compared. The release from CP-SA PM matrices was also investigated using three model drugs (paracetamol, salicylic acid, and verapamil HCl) and two dissolution media (0.1 N HCl or phosphate buffer, pH = 6.8), and the release rate, mechanism, and pH-dependence were characterized by fitting of Higuchi and Peppas models, and evaluation of similarity factor. Furthermore, swelling behavior of CP-SA matrix tablets was studied for evaluating its impact on drug release. RESULTS: The processing method (SD or PM) markedly affected the drug release from CP-SA matrices. ANOVA tests showed significant effects of the CP:SA ratio and drug type on the release rate (expressed by the constant, K(H), from Higuchi model) and of the dissolution medium on the release mechanism (expressed by the exponent, n, from Peppas model). Similarity factor (f2) indicated that the CP:SA ratios ≥ 25:75 and ≥ 50:50 were suitable for pH-independent release of paracetamol and salicylic acid, respectively, although for verapamil HCl, the matrix with low CP:SA ratio (0:100) showed remarkably reduced pH-dependence of release. Swelling parameters (water uptake and mass loss) were significantly changed with experimental variables (CP:SA ratio, medium, and time) and were in good correlation with drug release. CONCLUSION: Matrix tablets based on CP and SA form a potentially useful versatile system for pH-independent controlled drug release.

Preservation of nanostructured lipid carriers (NLC).

Due to their positive features (e.g., increased penetration of actives, re-enforcement of the lipid barrier and increase in skin hydration), nanostructured lipid carriers (NLC) are used in many dermal formulations. These formulations require preservation, and preservatives can impair the physical stability of disperse systems. Therefore, in this study, the influence of preservatives on the physical stability of Q10-loaded NLC was investigated using 11 different preservative mixtures. Whereas for nanosuspensions, only a limited number of preservatives are known from the literature not affecting their physical stability, a surprisingly high number of seven preservatives could be identified to be suitable for the preservation of NLC dispersions. For Q10-loaded NLC, Hydrolite 5 proved to be the best preservative, as it was found surprisingly to stabilize the NLC dispersion. Based on the data, a preservative classification system is suggested and a mechanistic model describing six key parameters affecting the physical stability of NLC could be developed. As most suitable characterization method to screen for suitable preservatives, light microscopy was identified. By being a simple, fast and cost efficient method, even extensive preservative screening studies can be performed very efficiently.

Sustained release tablets containing soluble polymethacrylates: comparison with tableted polymethacrylate IPEC polymers.

The objective of this study was to compare a novel sustained release tablet formulation that has the potential to be used for drugs of different physicochemical properties using a binary mixture of polymethacrylate polymers in their salt forms with the polymethacrylate interpolyelectrolyte complex (IPEC) tablets in terms of drug release and compactness. Also, we aimed to compare this formulation with an IPEC tablet in terms of drug release. Tablets prepared using Eudragit E-Citrate and Eudragit L-Sodium were more convenient, easier to prepare, and showed better sustained release and compactness characteristics compared to IPEC tablets of similar concentrations and preparation methods.

Recent patents review in microencapsulation of pharmaceuticals using the emulsion solvent removal methods.

Several methods and techniques are potentially useful for the preparation of polymeric microparticles in the broad field of microencapsulation. The preparation method determines the type and the size of microparticle and influence the ability of the interaction among the components used in microparticle formulations. This review is devoted to describe and allocate the recently awarded and pending patents regarding the technical and formulation innovations in microparticles involved in drug delivery that are based mainly on the emulsion solvent removal methods. The term microparticle designates systems larger than one micrometer in diameter and is used usually to describe both microcapsules and microspheres. Microparticle-containing drugs are employed for various purposes including--but not restricted to--controlled drug delivery, masking the taste and odor of drugs, protection of the drugs from degradation, and protection of the body from the toxic effects of the drugs. Polymeric carriers being essentially multidisciplinary are commonly utilized in microparticle fabrication and they can be of an erodible or a non-erodible type.

Investigations on the physical structure and the mechanism of drug release from an enteric matrix microspheres with a near-zero-order release kinetics using SEM and quantitative FTIR.

The objectives of this study were to evaluate the physical structure and the release mechanisms of theophylline microspheres made of Eudragit S 100 polymer as an enteric polymer, combined with a nonerodible polymer, Eudragit RL 100. In the preparation process, polymer combinations (1:1) were dissolved in an organic solvent mixture composed of acetone and methanol at a specific ratio containing a theoretical drug loading of approximately 15%. Two microsphere formulations (LS1 and LS2) were prepared at two different total polymer concentrations (10% in LS1 and 12.7% in LS2). Dissolution studies were carried out using US Pharmacopeia Dissolution Apparatus II in an acidic medium for 8 h and in an acidic medium (2 h) followed by a slightly basic-buffered medium for 10 h. Both LS1 and LS2 microsphere formulations produced particles that were spherical in shape and had very narrow size distributions with one size fraction comprising 70-80% of the yield. Scanning electron microscopy and quantitative Fourier transform infrared were used for microsphere physical structure evaluation. Except for the absence of drug crystals, photomicrographs of both LS microspheres after dissolution in pH 1.2 and 7.2 buffer solutions were similar to those before dissolution. Dissolution results indicated the ability of LS microspheres to minimize drug release during the acid stage. However, in the slightly basic medium that followed the acidic stage, the drug release was sustained and controlled in its kinetics and data fitted to Peppas equation indicated a case II transport suggesting that the drug release is mainly through swelling/erosion mechanism.

Novel combination of anionic and cationic polymethacrylate polymers for sustained release tablet preparation.

The objectives of this study were to prepare and evaluate a novel sustained release tablet formulation using a binary mixture of polymethacrylate polymers: Eudragit E-100 (EE) and Eudragit L-100 (EL) in their salt forms. Tablets prepared using EE-citrate and EL-Na showed the highest degree of swelling among other combinations of EE and EL. The drug release rates were independent of the pH of the dissolution medium as the release profiles exhibited a continuous release pattern with no burst effect when changing the pH of the medium. These results, along with other test results, indicated the presence of an ionic interaction between both polymers when combined in the salt forms.

Effect of the dispersion of Eudragit S100 powder on the properties of cellulose acetate butyrate microspheres containing theophylline made by the emulsion-solvent evaporation method.

The dispersion/incorporation of Eudragit S100 powder as a filler in cellulose acetate butyrate (CAB-551-0.01) microsphere containing theophylline was investigated as a means of controlling drug release. Microspheres of CAB-551-0.01 of different polymer solution concentrations/viscosities were prepared (preparations Z(0), Z(A), Z(B) and Z(C)) and evaluated and compared to microspheres of a constant concentration of CAB-551-0.01 containing different amounts of Eudragit S100 powder as a filler (preparations X(A), X(B) and X(C)). The organic solvent acetonitrile used was capable of dissolving the matrix former CAB-551-0.01 only but not Eudragit S100 powder in the emulsion-solvent evaporation method. The CAB-551-0.01 concentration in Z(A), Z(B) and Z(C) was equal to the total polymer concentration (CAB-551-0.01 and Eudragit S100 powder) in X(A), X(B) and X(C), respectively. Scanning electron microscopy (SEM) was used to identify microspheres shape and morphology. In vitro dissolution studies were carried out on the microspheres at 37 degrees C (+/-0.5 degrees C) at two successive different pH media (1.2 +/- 0.2 for 2 h and 6.5 +/- 0.2 for 10 h). Z preparations exhibited low rates of drug release in the acidic and the slightly neutral media. On the other hand, X preparations showed an initial rapid release in the acidic medium followed by a decrease in the release rate at the early stage of dissolution in the slightly neutral pH which could be due to some relaxation and gelation of Eudragit S100 powder to form a gel network before it dissolves completely allowing the remained drug to be released.

Preparation and evaluation of Eudragit S 100 microspheres as pH-sensitive release preparations for piroxicam and theophylline using the emulsion-solvent evaporation method.

Microencapsulation of the anti-inflammatory drug piroxicam and the anti-asthmatic drug theophylline was investigated as a means of controlling drug release and minimizing or eliminating local side effects. Microspheres of both drugs that are different in the chemical nature and size were successfully encapsulated at a theoretical loading of 25% with the pH sensitive Eudragit S 100 polymer using the emulsion-solvent evaporation method. Solvent composition, stirring rate and the volume of the external phase were adjusted to obtain reproducible, uniform and spherical microspheres. The size distribution of microsphere batches generally ranged from 125-500 microm with geometric means close to 300 microm. Optical light microscopy was used to identify the microsphere shape. Drug loading was determined by completely dissolving the microspheres in an alkaline borate buffer at pH 10. In vitro dissolution studies were carried out on the microspheres at 37 degrees C (+/-0.5 degrees C) at 100 rpm with USP Dissolution Apparatus II using the procedure for enteric-coated products at two successive different pH media (1.2 and 6.5). Both preparations exhibited an initial rapid release in the acidic medium with theophylline showing a larger increase in the amount released during this stage. The drug release was sustained for both preparations at pH 6.5 with theophylline microspheres, showing more extended release. Drug release rate kinetics followed a Higuchi spherical matrix model for both microsphere preparations.