Ethanol-induced dose dumping from sodium alginate matrix tablets: Investigation of the effects of medium viscosity and pH.

In this work, the swelling and disintegration of drug-free sodium alginate (SA) compacts and the release of metformin HCl from SA matrix tablets were investigated in acidic media of different ethanol concentrations (0, 10, 20, and 40 % v/v), pH (1.2 and 4.5) and HPMC K4M concentrations (0-1 % w/v). The investigated dissolution media represented the consumption of different alcoholic beverages, the pH of fasted and fed states, and a range of viscosity resembling diluted homogenized FDA meal. The dissolution efficiency and the time to 50 % release (t50%) were selected as release parameters. It was found that both ethanol concentration and medium pH affected drug release from SA matrix tablets and the swelling of SA compacts. Dose dumping occurred at high ethanol concentration (40 %) at both media pH with almost complete drug release within 15-30 min associated with rapid matrix disintegration. HPMC at 0.5-1 % concentrations increased the medium's viscosity, preventing dose dumping at high ethanol concentrations. Erosion and disintegration of SA compacts were decelerated by increasing HPMC concentration in hydroethanolic media in consonance with decreased release rate from matrix tablets. ANOVA tests showed significant effects of pH and concentrations of ethanol and HPMC in the dissolution medium on the release parameters.

Co-spray Drying Drugs with Aqueous Polymer Dispersions (APDs)-a Systematic Review.

Aqueous colloidal dispersions of water-insoluble polymers (APDs) avoid hassles associated with the use of organic solvents and offer processing advantages related to their low viscosity and short processing times. Therefore, they became the main vehicle for pharmaceutical coating of tablets and multiparticulates, a process commonly employed using pan and fluidized-bed machinery. Another interesting although less common processing approach is co-spray drying APDs with drugs in aqueous systems. It enables the manufacture of capsule- and matrix-type microspheres with controllable size and improved processing characteristics in a single step. These microspheres can be further formulated into different dosage forms. This systematic review is based on published research articles and aims to highlight the applicability and opportunities of co-spray drying drugs with APDs in drug delivery.

siRNA as a Potential Therapy for COVID-19.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) is a highly contagious virus causing COVID-19 disease that severely impacted the world health, education, and economy systems in 2020. The numbers of infection cases and reported deaths are still increasing with no specific treatment identified yet to halt this pandemic. Currently, several proposed treatments are under preclinical and clinical investigations now, alongside the race to vaccinate as many individuals as possible. The genome of SARS-CoV2 shares a similar gene organization as other viruses in the Coronaviridae family. It is a positive-sense, single-stranded RNA. This feature suggests that RNA interference (RNAi) is an attractive prophylactic and therapeutic option for the control of this pandemic and other possible future pandemics of the corona viruses. RNAi utilizes the use of siRNA molecules, which are 21-29 nt duplexes RNA molecules that intervene with targeted gene expression in the cytoplasm by a specific mechanism of complementary destruction of mRNA. Previous experience with SARS-CoV and the Middle East respiratory syndrome (MERS) showed that siRNA molecules were effective against these viruses in vitro and in vivo. Moreover, there have been extensive advances in siRNA technology in the past decade from chemistry and target selection considerations; which concluded with the successful approval of two commercial products based on siRNA technology. In addition, the current knowledge of the genome structure and functionality of the corona viruses enables the recognition of conserved sequences to optimize siRNA targeting and avoid viral escape through mutations, either for the current SARS-CoV2 as well as future corona viruses.

Co-Spray Drying of Paracetamol and Propyphenazone with Polymeric Binders for Enabling Compaction and Stability Improvement in a Combination Tablet.

Paracetamol (PCT) and propyphenazone (PRP) are analgesic drugs that are often combined in a single dosage form for enhanced pharmacological action. In this work, PCT and PRP were co-spray dried separately with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) using drug suspensions in polymer solutions as feed liquids. It was thought that because of polymer adherence to the surface of drug particles, the risk of PCT-PRP contact and interaction could be reduced. Such interaction may be caused by localized temperature gradients due to frictional forces during tableting, or during storage under harsh conditions. A worst-case scenario would be eutectic formation due to variations in powder mixture homogeneity since eutectic and therapeutic mass PCT/PRP ratios are close (65:35 and 60:40, respectively) and eutectic temperature is low (~56 °C). Uniform particle size, round shape, compaction improvement and faster release of the analgesics were important additional benefits of co-spray drying. Experimental design was first applied for each drug to optimize the polymer concentration on the yield of spray drying and melting point separation (Δmp) of heated binary mixtures of co-spray dried PCT/neat PRP, and vice versa, with the two drugs always included at their therapeutic 60:40 ratio. Optimal combinations with largest Δmp and production yield were: co-spray dried PCT (15% HPC) with neat PRP and co-spray dried PRP (10% HPMC) with neat PCT. Compression studies of these combinations showed tableting improvement due to the polymers, as reflected in greater work of compaction and solid fraction, greater fracture toughness and tablet strength, easier tablet detachment from the punch surface and ejectability. Faster release of both drugs was obtained from the tablet of co-spray dried PCT (15% HPC) with neat PRP. A one-month stability test (75% RH/40 °C) showed moisture-induced alteration tablet strength.

Spray drying of naproxen and naproxen sodium for improved tableting and dissolution - physicochemical characterization and compression performance.

In this work, the tabletability and dissolution of spray-dried forms of naproxen and its sodium salt were compared with those of unprocessed drugs. Solutions of naproxen or naproxen sodium alone or with HPMC (5% w/w of drug content) were spray dried. Scanning electron micrographs showed that naproxen sodium spray-dried particles were spherical, whereas those of naproxen were non-spherical but isodiametric. Powder x-ray diffraction and thermal analysis indicated that co-spray drying with HPMC resulted in reduced crystallinity of naproxen and higher naproxen sodium dihydrate content. FTIR and Raman analysis showed shifting, merging or elimination of bands in the spectra of the co-spray dried products signifying solid-state alterations. When mixed with suitable processing aids (7% w/w), all co-spray dried powders produced satisfactory tablets in the pressure range 73-295 MPa. Conversely, physical mixtures of naproxen compressed with the same aids failed tableting, whereas naproxen sodium produced weak tablets. Dissolution tests showed significant improvement for co-spray dried drugs tablets. Therefore, since the large therapeutic doses of naproxen and sodium naproxen limit the use of tableting aids, the improved compaction and dissolution performance of the spray-dried forms may be a formulation alternative.

Mechanical properties of starch esters at particle and compact level - Comparisons and exploration of the applicability of Hiestand's equation to predict tablet strength.

Hydrophobic starch esters have potential as tablet matrix formers in controlled drug delivery. The mechanical properties of native starch (SN), starch acetate (SA) and starch propionate (SP) were studied at particle and compact level. Particle microhardness and modulus of elasticity were evaluated by nanoindentation. Force-displacement data of compressed powder were analyzed using Heckel in conjunction with piecewise regression, Kuentz-Leuenberger, Kawakita and Adams models, and yield pressure parameters were derived. Starches were characterized for chemical structure by Raman spectroscopy, crystallinity from powder x-ray diffraction (PXRD) patterns and surface energy from apparent contact angle measurements. A-type starch reflections were absent in the PXRDs of esters indicating greater amorphicity. Consequently, the particle microhardness of starch esters decreased leading to greater deformation during compaction and lower values of yield pressure parameters. These parameters increased with microhardness and ranked the starches in the order: SP < SA < SN. Fitting the experimental data into Hiestand's bonding index equation, a linear correlation (R2 = 0.902) was established between experimental and calculated tablet strength describing results of all starches, when Adams (το') yield pressure was used as the 'effective compression pressure' in the above equation.

The use of design of experiments to develop hot melt extrudates for extended release of diclofenac sodium.

The effect of formulation and processing parameters on processability and release from hot-melt extrusion (HME)-based matrices appears to be API and polymer dependent. Accordingly, the aim of this work was to design an extended-release formulation of diclofenac sodium by using HME technique and design of experiment (DoE). The extrudates were prepared using a vertical lab-scale single screw extruder. A D-optimal design with 16 formulations was employed to evaluate and model the effect of diclofenac sodium, ethyl cellulose and Natrosol L levels on the release profile. The percentage of drug release at 2, 4, 8 and 16 h were the dependent variables. The formulation factors that affect drug release were identified and satisfactorily modeled. The goodness of fit (R2) and goodness of prediction (Q2) parameters obtained for release responses were 0.913 and 0.682 at 2 h, 0.946 and 0.67 at 4 h, 0.942 and 0.658 at 8 h, and 0.892 and 0.673 at 16 h, respectively. The design space of optimal fractions of ethyl cellulose and Natrosol L at various drug levels was successfully constructed by response surface methodology. In conclusion, the DoE approach helped to identify and quantify formulation variables that affect the release of diclofenac sodium from HME-based formulation.

Ethanol effect on acid resistance of selected enteric polymers.

The aim of this study was to investigate under in vitro conditions the influence of ethanol on acid resistance of four commercially-available enteric polymers (Acryl-EZE®, AQOAT®, Hypromellose phthalate, and Sureteric®). For this purpose, custom-prepared paracetamol tablets were coated with the enteric polymers and tested for release using the buffer-addition method. Ten different hydro-ethanolic media were used in the acid stage corresponding to five levels of ethanol (0, 5, 10, 20, and 40% v/v) in two acidic solutions representing low and high gastric pH (0.1 N HCl pH 1.2, LGpH, and phosphate buffer pH 4.0, HGpH, respectively). The coats were found to resist both types of acidic solution with ethanol percentages up to 10% leading to release profiles that conformed with the pharmacopeial requirements (<10% release after 2 h in acid stage) except for Acryl-EZE®, which showed a premature release in HGpH media. At the higher ethanol levels (20 and 40%), premature release associated with increased acid uptake by coated tablets was noticed for all polymers and more remarkably in HGpH media. ANOVA tests revealed significant effects of polymer type, acidic solution type, and ethanol level on the onset and extent of premature release.

Evaluation of Spironolactone Solid Dispersions Prepared by Co-Spray Drying With Soluplus® and Polyvinylpyrrolidone and Influence of Tableting on Drug Release.

Solid dispersions of spironolactone with Soluplus® and polyvinylpyrrolidone were prepared by spray drying according to a mixture experimental design and evaluated for moisture content, particle size, drug solubility, crystallinity (powder X-ray diffraction and differential scanning calorimetry), and physicochemical interactions (Fourier-transform infrared spectroscopy, Raman). In vitro dissolution was evaluated for the spray dried product itself and after compression into tablets, and prediction models were derived using multiple linear regression analysis. The spray dried products consisted of amorphous drug, indicated by the absence of crystalline powder X-ray diffraction peaks. Amorphization and interactions impacted changes in the Fourier-transform infrared spectroscopy spectra in the ranges 2900-3000 cm-1 (C-H) and 1600-1800 cm-1 (C=O) and caused merging at 1690 cm-1 (C=O of lactone) and 1670 cm-1 (C=O of thioacetyl group). In the Raman spectra, amorphization and interactions resulted in disappearance of peak at 1690 cm-1 (C=O) and merging of peaks at 582 and 600 cm-1 (C-S). Hydrogen bonding between the thioacetyl group of the drug with the hydroxyl groups of Soluplus® caused marked suppression of the peak at 1190 cm-1 (R-C(=O)-S vibration). Amorphization and interactions resulted in improved solubility and dissolution which was greatest for drug/Soluplus® ratio 1:4 and was also demonstrated in the corresponding tablets.

Sustained release of diltiazem HCl tableted after co-spray drying and physical mixing with PVAc and PVP.

In this work, aqueous diltiazem HCl and polyvinyl-pyrrolidone (PVP) solutions were mixed with Kollicoat SR 30D and spray dried to microparticles of different drug:excipient ratio and PVP content. Co-spray dried products and physical mixtures of drug, Kollidon SR and PVP were tableted. Spray drying process, co-spray dried products and compressibility/compactability of co-spray dried and physical mixtures, as well as drug release and water uptake of matrix-tablets was evaluated. Simple power equation fitted drug release and water uptake (R(2) > 0.909 and 0.938, respectively) and correlations between them were examined. Co-spray dried products with PVP content lower than in physical mixtures result in slower release, while at equal PVP content (19 and 29% w/w of excipient) in similar release (f2 > 50). Increase of PVP content increases release rate and co-spray drying might be an alternative, when physical mixing is inadequate. Co-spray dried products show better compressibility/compatibility but higher stickiness to the die-wall compared to physical mixtures. SEM observations and comparison of release and swelling showed that distribution of tableted component affects only the swelling, while PVP content for both co-spray dried and physical mixes is major reason for release alterations and an aid for drug release control.

Optimization of pH-independent chronotherapeutic release of verapamil HCl from three-layer matrix tablets.

The aim of this work was to evaluate and optimize formulation of three-layer matrix tablets based on xanthan gum (XG) and sodium alginate for chronotherapeutic pH-independent release of verapamil HCl (VH). Artificial neural networks (ANN) were applied in the optimization and compared with multiple linear regression (MLR). A face-centered central composite experimental design was employed with three factors (mass fraction of VH in intermediate layer, X1, and of XG in matrix former of intermediate and outer layers, X2 and X3). The prepared tablets were tested for in vitro release in 0.1 N HCl and phosphate buffer (pH 7.5), tensile strength and friability. Furthermore, swelling observation and release modeling to Weibull function and power law equation of Peppas were employed to help further understanding of release behavior and mechanism. The releases (%) in phosphate buffer (pH 7.5) at 6, 12 and 24 h were selected as responses to depict the mode of release and similarity factor (f2), between release profiles in 0.1N HCl and pH 7.5 during the first 8 h, as response of pH-independence. A desirability function combining the four responses was constructed and overall desirability values were used for the ANN and MLR modeling. Five additional checkpoint formulations, within the experimental domain, were used to validate the external predictability of the models. The constructed ANN model fitted better to the overall desirability than the MLR model (R=0.838 vs. 0.670, for the additional checkpoint formulations) and therefore, was used for prediction of formulation with optimal in vitro drug release.

Influence of ethanol on swelling and release behaviors of Carbopol(®)-based tablets.

The aim of this work was to investigate the effect of ethanol on the in vitro swelling and release behaviors of Carbopol(®)-based tablets. The swelling behavior of drug-free compacts and the release of model drugs (metformin HCl, caffeine and theophylline) from matrix tablets were evaluated in acidic and buffered media with 0, 20 and 40% (v/v) ethanol. Release data were analyzed by fitting to Higuchi and Peppas models and calculation of similarity factor (f2). ANOVA tests were performed to determine significant factors on swelling and release. It was found that ethanol affects swelling and erosion of drug-free Carbopol(®) compacts, and the effect was highly dependent on medium pH. For matrix tablets, no dose dumping due to ethanol was manifested. The release rate and mechanism, however, were significantly affected by ethanol concentration as indicated by ANOVA applied to the constant, KH, from Higuchi model and the exponent, n, from Peppas model, respectively. The effect of ethanol on release was further confirmed by similarity factor results, which indicated that ethanol led to different release profiles (f2 < 50) in seven of eight cases for matrices containing metformin HCl and in three of eight cases for matrices containing caffeine and theophylline.

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.

Optimization of extended-release hydrophilic matrix tablets by support vector regression.

BACKGROUND: In this work, support vector regression (SVR) was applied to the optimization of extended release from swellable hydrophilic pentoxifylline matrix-tablets and compared to multiple linear regression (MLR). METHODS: Binary mixtures comprising ethylcellulose and sodium alginate were used as the matrix-former. The matrix-former : drug weight ratio and the percentage of sodium alginate in the matrix-former were the formulation factors (independent variables) and the percentages of drug release at four different time intervals were the responses (dependent variables). Release was determined according to United States Pharmacopeia 31 for 11 pentoxifylline matrix-tablet formulations of different independent variable levels and the corresponding results were used as tutorial data for the construction of an optimized SVR model. Six additional checkpoint matrix-tablet formulations, within the experimental domain, were used to validate the external predictability of SVR and MLR models. RESULTS: It was found that the constructed SVR model fitted better to the release data than the MLR model (higher coefficients of determination, R( 2), lower prediction error sum of squares, narrower range of residuals, and lower mean relative error), outlining its advantages in handling complex nonlinear problems. Superimposed contour plots derived by using the SVR model and describing the effects of polymer and sodium alginate content on pentoxifylline release showed that formulation of optimal release profiles, according to United States Pharmacopeia limitations, could be located at drug : matrix ratio of 1 and sodium alginate content 25% w/w in the matrix-former. CONCLUSION: The results indicate the high potential for SVR in formulation development and Quality by Design.

Sustained-release of buspirone HCl by co spray-drying with aqueous polymeric dispersions.

Sustained-release of buspirone HCl (BUH) was attempted by spray drying after dissolving in two commercially available aqueous polymeric dispersions (Eudragit RS 30 D or Kollicoat SR 30 D) at five different drug:polymer ratios (1:1, 1:2, 1:3, 1:6 and 1:9). The produced spray-dried agglomerates were evaluated in terms of their particle size and morphology, production yield, encapsulation efficiency and in-vitro release of BUH. Possible drug-polymer interactions were checked by Differential Scanning Calorimetry (DSC) and FT-IR spectroscopy. Scanning electron microscopy (SEM) was employed for the qualitative characterization of particle size and morphology. Encapsulation efficiency was generally high (around 100%) and independent of the polymeric dispersion type, while production yield was generally low (7.2-31.0%) and significantly lower for the case of Kollicoat SR 30 D (KSR) than for Eudragit RS 30 D (ERS). Scanning electron micrographs showed remarkable changes in size and shape of agglomerates due to the type of aqueous polymeric dispersion and drug:polymer ratio. In-vitro release of BUH from compacted co spray-dried agglomerates was remarkably slower and incomplete for the case of Kollicoat at drug:polymer ratio below 1, presumably due to increased plastic deformation of the developed coating instead of fragmentation in the case of Eudragit coating during compaction.