Effect of particle size and diluent type on critical parameters for disintegration of tablets containing croscarmellose sodium as a disintegrant

Purpose: The aim of the present work was to determine the effect of particle size and type of diluents on critical concentration for the disintegration of tablet formulations containing a physical binary mixture of a superdisintegrant (croscarmellose sodium, CS) and a diluent.Methods: The diluents used in this study were microcrystalline cellulose (MCC), dibasic calcium phosphate (DCP) and pregelatinized starch (PGS). Each diluent was divided into 2 different size ranges (small and large size)) and further mixed with 0 - 100 % CS. The binary mixture was compressed at controlled pressure, and the disintegration time and physical characteristic of the tablets were evaluated.Results: The point of CS concentration that markedly affected the disintegration time of the tablets was recorded as the critical concentration for disintegration. The results showed that the particle size of the diluent did not affect the disintegration time. The critical CS concentrations were 2 % for DCP and MCC tablets and 5 % for PGS tablet. Adding a small amount of CS improved the disintegration of the tablets. However, increasing the amount of CS in the formulation also affected the hardness of the tablets. The particle size of diluents had a significant effect on the critical concentration for tablet disintegration.Conclusion: Determining the type and appropriate amounts of diluent and disintegrant (percolating component) may be useful in the design of tablet formulations.Keywords: Disintegration, Percolation threshold, Croscarmellose sodium, Microcrystalline cellulose, Dibasic calcium phosphate, Pre-gelatinized starc

Preparation and assessment of poly(methacrylic acid-coethylene glycol dimethacrylate) as a novel disintegrant

Purpose: To prepare and evaluate poly(methacrylic acid (MAA)-co-ethylene glycol dimethacrylate (EGD)) as a tablet disintegrant.Methods: Poly(MAA-co-EGD) in acid (H) and sodium (Na) forms at cross-linker (EGD) levels of 0.25 -16 % were synthesized and subjected to Fourier transform infrared spectroscopy. Swelling capacity, disintegration efficiency and cytotoxicity to Caco-2 cells were determined using standard procedures.Results: Poly(MAA-co-EGD) in acid (H) and sodium (Na) forms were successfully prepared. In contact with water, the polymers in Na form swelled more than those in H form. The swelling capacities of polymers in H and Na forms decreased with increasing amounts of cross-linker. Incorporation of the polymers accelerated the disintegration of microcrystalline cellulose tablets (placebo), and the disintegration efficiency depended on the salt form and amount of cross-linker. The Na salt form of the polymer crosslinked at 16 % EGD was the best candidate disintegrant. When used at 2.5 and 10 %, the selected polymer effectively promoted the disintegration and drug release of propranolol hydrochloride tablets. Moreover, cytotoxicity tests showed that it was non-toxic to Caco-2 cells.Conclusion: The developed poly(MAA-co-EGD) possesses good disintegration and dissolution functionalities. Thus, it may be adopted as a new super-disintegrant for fast-release tablets.Keywords: Tablet disintegrant, Methacrylic acid, Ethylene glycol dimethacrylate, Propranolol hydrochlorid

Preparation and characterization of N-benzyl-N,O-succinyl chitosan polymeric micelles for solubilization of poorly soluble non-steroidal anti-inflammatory drugs

Purpose: To investigate the solubilization of poorly water-soluble non-steroidal  anti-inflammatory drugs (NSAIDs) in N-benzyl-N,O-succinyl chitosan (BSCS)  polymeric micellesMethods: BSCS was synthesized by reductive amination and succinylation,  respectively. NSAIDs; meloxicam (MX), piroxicam (PRX), ketoprofen (KP) and indomethacin (IND) were entrapped in the hydrophobic inner cores by evaporation method. The effects of drug structure on loading efficiency, particle size and surface charge of micelles were investigated.Results: The critical micelle concentration of BSCS micelles was 0.0385 mg/mL and cytotoxicity on Caco-2 cells depends on the polymer concentration (IC50 = 3.23 ± 0.08 mg/mL). BSCS micelles were able to entrap MX, PRX, KP and IND and also improve the solubility of drugs. Drug loading efficiency was highly dependent on the drug molecules. The drug loading capacity of these BSCS micelles was in the following rank order: KP (282.9 μg/mg) > PRX (200.8 μg/mg) > MX (73.7 μg/mg) > IND (41.2 μg/mg). The highest loading efficiency was observed in KP-loaded BSCS micelles due to the attractive force between phenyl groups of KP and benzyl groups of the polymer. Particle size and surface charge were in the range of 312 - 433 nm and -38 to -41 mV, respectively.Conclusion: BSCS copolymer presents desirable attributes for enhancing the  solubility of hydrophobic drugs. Moreover, BSCS polymeric micelles might be beneficial carrier in a drug delivery system.Keywords: BSCS, polymeric micelles, solubilization, non-steroidal anti-inflammatory drug

Fabrication of Cationic Exchange Polystyrene Nanofibers for Drug Delivery

Purpose: To prepare polystyrene nanofiber ion exchangers (PSNIE) with surface cation exchange functionality using a new method based on electrospinning and also to optimize crosslinking and sulfonation reactions to obtain PSNIE with maximum ion exchange capacity (IEC).Method: The nanofibers were prepared from 15% w/v polystyrene solution in dimethylacetamide (DMAc) containing 0.025 %w/v tetrabutylammonium bromide (TBAB) using electrospinning technique, followed by crosslinking with sulfuric acid/formaldehyde in a ratio ranging from 100/0 to 50/50 v/v and sulfonation in sulfuric acid. Degree of crosslinking was determined as the amount of fibers that remained in dichloromethane. The morphology and diameter of the fibers were evaluated by scanning electron microscopy (SEM) while IEC of PSNIE was performed by salt splitting titration.Results: PSNIE crosslinked with a sulfuric acid/formaldehyde ratio of 90/10 with 0.1 %w/v silver sulfate for 10 min at 70°C and sulfonated in 98 % sulfuric acid with 0.2 %w/v silver sulfate as the catalyst at 100°C for 30 min showed a maximum IEC of 3.21 meq/g-dry-PSNIE. Increase in  sulfonation temperature caused the IEC of PSNIE to increase due to faster sulfonation. It was observed that the higher the temperature the faster the rate of sulfonation reaction. The diameter of the fibers after sulfonation was 404 ± 42 nm.Conclusion: These results indicate that PSNIE can be successfully prepared by electrospinning. Furthermore, cationic drug can be loaded onto the novel PSNIE for controlled release delivery.Keywords: Polystyrene, Ion exchange capacity, Nanofibers, Ion exchangers, Crosslinking, Sulfonation

Taste Masking and Molecular Properties of Metformin Hydrochloride-Indion 234 Complexes

Metformin hydrochloride is an oral antidiabetic biguinide agent, used in the management of non-insulin-dependent (type-2) diabetes mellitus. The purpose of present work was to formulate tasteless complexes of metformin hydrochloride with indion 234 and to evaluate molecular properties of drug complexes. The drug loading onto ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug to resin, and temperature. Drug resin complexes (DRC) were evaluated for taste masking and characterized by x-ray diffraction study and infrared spectroscopy. Metformin hydrochloride release from DRC is obtained at salivary and gastric pH and in the presence of electrolytes. The efficient drug loading was evident in batch process using activated indion 234 with a pH of 3.5 and drug-resin ratio of 1:1.2, while temperature enhances the complexation process. Infrared spectroscopy revealed complexation of –NH (drug) with indion 234. DRC are amorphous in nature. Drug release from DRC in salivary pH was insufficient to impart bitter taste. Volunteers rated the complex as tasteless and agreeable. Complete drug release was observed at gastric pH in 3 h. The drug release was accelerated in the presence of electrolytes. Indion 234 is inexpensive, and the simple technique is effective for bitterness masking of metformin

Formulation and Characterization of Patient-Friendly Dosage Form of Ondansetron Hydrochloride

Ondansetron hydrochloride is an intensely bitter antiemetic drug used to treat nausea and vomiting following chemotherapy. The purpose of the present work was to mask the taste of ondansetron hydrochloride and to formulate its patient-friendly dosage form. Complexation technique using indion 234 (polycyclic potassium with carboxylic functionality) and an ion-exchange resin was used to mask the bitter taste and then the taste-masked drug was formulated into an orodispersible tablet (ODT). The drug loading onto the ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug to resin and temperature. The resinate was evaluated for taste masking and characterized by X-ray diffraction study and infrared spectroscopy. ODTs were formulated using the drug–resin complex. The developed tablets were evaluated for hardness, friability, drug content, weight variation, content uniformity, friability, water absorption ratio, in vitro and in vivo disintegration time and in vitro drug release. The tablets disintegrated in vitro and in vivo within 24 and 27 s, respectively. Drug release from the tablet was completed within 2 min. The obtained results revealed that ondansetron HCl has been successfully taste masked and formulated into an ODT as a suitable alternative to the conventional tablets

Evaluation of a Weakly Cationic Exchange Poly (Methacrylic Acid-Co-Divinylbenzene) Resin as Filler-Binder for Direct Compression Tablets

Purpose: To evaluate a weakly cationic exchange poly(methacrylic acid-co-divinylbenzene) resin (PMD) as a new filler-binder for direct compression tablets. Methods: Powder properties of PMD and MCC were characterized. Tablets made from PMD and MCC with and without propranolol hydrochloride were evaluated for diameter, thickness, friability, assay, disintegration, dissolution and compression behavior. Results: Tablets made from PMD (thickness: 3.54 - 4.46 mm) were thicker than those of MCC (2.93 - 3.33 mm). At compression pressures ≥ 309 MPa, the crushing strength of PMD tablets was so high that it exceeded the capacity of the tester (500 N). PMD tablets rapidly disintegrated (0.43 - 9.56 min), but MCC tablets did not disintegrate within 60 min. The crushing strength of PMD tablets containing 10 and 100 mg propranolol hydrochloride was 406.1 and 177.9 N, respectively, which were lower than that of tablets without the drug. Tablets made from PMD also exhibited faster drug dissolution. The slopes of the linear portions of Heckel plots for PMD and MCC were comparable (5.02×10-3 and 5.12×10-3 MPa-1), respectively. Conclusion: PMD has good compressibility at high compression pressures, which should make it a suitable filler-binder for direct compression tablet

Evaluation of some anionic exchange resins as potential tablet disintegrants

Purpose: To determine the potential of some anionic exchange resins as tablet disintegrants.Methods: Dowex1® x2, x4 and x8 resins (crosslinked copolymers of styrene and divinylbenzene with quaternary methyl amine functionality) were evaluated as disintegrant for dibasic calcium phosphate dihydrate tablets. The best resin providing the fastest disintegration and highest hardness of obtained tablets was selected for further investigation. The effect of resin concentration and compression force on the properties of tablets using the selected resin was investigated. In addition, the disintegrant efficacy of the selected resin in the tablet formulations containing either a basic drug, e.g., dextromethorphan hydrobromide (DMP), or an acidic drug, e.g., diclofenac sodium (DCN), was determined in comparison with sodium starch glycolate (SSG).Results: Dowex1®x2 resin exhibited the fastest disintegration (6.0 s) and the highest hardness (103.6 N) of obtained tablets. These disintegrating and tablet properties depended upon the resin concentration and compression force. For DMP, the resin provided faster disintegration and drug release (8.0 s and 100.4 % at 10 min) as compared with SSG (16.2 s and 98.9 % at 30 min). In contrast, the resin caused the depleted release of DCN (61.6 % at 120 min) in spite of providing the faster tablet disintegration (10.0 s) than SSG (15.5 s) due to the ionic binding of the drug and resin.Conclusion: The Dowex1®x2 resin was shown to be a potential disintegrant for the tablets of basic drugs.Keywords: Anionic exchange resin, Disintegrant, Dextromethorphan hydrobromide, Diclofenac sodium, Calcium phosphat

Development and Optimization of <i>Andrographis paniculata</i> Extract-Loaded Self-Microemulsifying Drug Delivery System Using Experimental Design Model

The objectives of this study were to develop an optimized formulation for an Andrographis paniculata extract (AGPE)-loaded self-microemulsifying drug delivery system (SMEDDS) using an experimental design and evaluate the characteristics of the developed SMEDDS. The solubility of andrographolide (AGP) in various solvents was investigated. The pseudo-ternary phase was constructed to provide an optimal range for each component to form microemulsions (MEs). The formulation was optimized using an I-optimal design mixture type, where the physical stability, droplet size, polydispersity index, and zeta potential were examined. Soft capsules of the optimized AGPE-loaded SMEDDS were manufactured. The dissolution and ex vivo membrane permeation were studied. Oleic acid, Tween® 80, and PEG 400 were the best solubilizers for AGP. The promising surfactant to co-surfactant ratio to generate ME was 3:1. The optimized SMEDDS contained 68.998% Tween® 80, with 13.257% oleic acid and 17.745% PEG 400. The assayed content of AGP, uniformity of dosage unit, and stability complied with the expected specifications. The dissolution and membrane permeability of AGPE-loaded SMEDDS was significantly improved from the A. paniculata extract (p < 0.05). All in all, the developed optimized AGPE-loaded SMEDDS was proven to contain optimal composition and AGP content where a stable ME could spontaneously be formed with enhanced delivery efficacy