Co-crystallization for enhanced dissolution rate of bicalutamide: preparation and evaluation of rapidly disintegrating tablets

Objectives: Enhance the dissolution rate of bicalutamide via co-crystallization with sucralose (sweetener), with the aim to develop rapidly disintegrating tablets with subsequent prompt dissolution.

Significance: Bicalutamide is antiandrogenic agent for the treatment of prostate cancer but has low and variable oral bioavailability, mainly attributed to poor dissolution. Co-crystallization with benign excipients is promising for dissolution enhancement with the additive serving dual functions. The benefit will become greater if dissolution enhancement is associated with the development of orodispersible tablets which is suitable for elderly patients who are the most vulnerable for prostate cancer.

Methods: Bicalutamide was dissolved in acetone in the presence of increasing molar ratios of sucralose. The solvent was evaporated while mixing to deposit crystals that were subjected to wet co-grinding until drying. The developed solids were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and X-ray diffraction in addition to monitoring bicalutamide dissolution.

Results: Instrumental analysis provided evidences for co-crystallization which was initiated at 1:1 molar ratio of bicalutamide to sucralose with complete co-crystallization at 1:4 molar ratio. The co-crystals provided faster bicalutamide dissolution compared with the unprocessed drug and that recrystalized from acetone in the absence of sucralose. The formulation containing bicalutamide with sucralose at 1:4 molar ratio was selected for tablet formulation into which superdisintegrants were included. The developed tablets exhibited flash disintegration with subsequent fast dissolution of bicalutamide.

Conclusions: The study introduced co-crystallization of bicalutamide with sucralose as an efficient tool to enhance the dissolution rate and to develop rapidly dissolving tablets for intraoral administration.     

Formulation studies for mirtazapine orally disintegrating tablets

Abstract

Objective: Orally disintegrating tablets (ODTs) recently have gained much attention to fulfill the needs for pediatric, geriatric, and psychiatric patients with dysphagia. Aim of this study was to develop new ODT formulations containing mirtazapine, an antidepressant drug molecule having bitter taste, by using simple and inexpensive preparation methods such as coacervation, direct compression and to compare their characteristics with those of reference product (Remereon SolTab).

Materials and methods: Coacervation method was chosen for taste masking of mirtazapine. In vitro characterization studies such as diameter and thickness, weight variation, tablet hardness, tablet friability and disintegration time were performed on tablet formulations. Wetting time and in vitro dissolution tests of developed ODTs also studied using 900?mL 0.1?N HCl medium, 900?mL pH 6.8 phosphate buffer or 900?mL pH 4.5 acetate buffer at 37?±?0.2?°C as dissolution medium.

Results: Ratio of Eudragit® E-100 was chosen as 6% (w/w) since the dissolution profile of A1 (6% Eudragit® E-100) was found closer to the reference product than A2 (4% Eudragit® E-100) and A3 (8% Eudragit® E-100). Group D, E and F formulations were presented better results in terms of disintegration time. Dissolution results indicated that Group E and F formulations showed optimum properties in all three dissolution media.

Discussion: Formulations D1, D4, D5, E3, E4, F1 and F5 found suitable as ODT formulations due to their favorable disintegration times and dissolution profiles.

Conclusion: Developed mirtazapine ODTs were found promising in terms of showing the similar characteristics to the original formulation.     

Sucralose as co-crystal co-former for hydrochlorothiazide: development of oral disintegrating tablets

Development of oral disintegrating tablets requires enhancement of drug dissolution and selection of sweetener. Co-crystallization of drugs with inert co-former is an emerging technique for enhancing dissolution rate. The benefit of this technique will become even greater if one of the sweeteners can act as co-crystal co-former to enhance dissolution and mask the taste. Accordingly, the objective of this work was to investigate the efficacy of sucralose as a potential co-crystal co-former for enhancing the dissolution rate of hydrochlorothiazide. This was extended to prepare oral disintegrating tablets. Co-crystallization was achieved after dissolving hydrochlorothiazide with increasing molar ratios of sucralose in the least amount of acetone. The co-crystallization products were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and powder X-ray diffraction. These measurements indicated that co-crystallization process started at a drug sucralose molar ratio of 1:1 and completed at 1:2. The developed co-crystals exhibited faster drug dissolution compared with the control, with co-crystal containing the drug with sucralose at 1:2 molar ratio being optimum. The later was used to prepare fast disintegrating tablets. These tablets had acceptable physical characteristics and showed fast disintegration with subsequent rapid dissolution. The study introduced sucralose as co-crystal co-former for enhanced dissolution and masking the taste.     

Development and optimization of taste-masked orally disintegrating tablets (ODTs) of clindamycin hydrochloride

The purpose of this research was to develop an orally disintegrating tablet (ODT) dosage form containing taste-masked beads of clindamycin HCl. Several formulation strategies were evaluated and a taste-masked ODT of clindamycin HCl was prepared without the use of a waxy cushioning agent. Clindamycin HCl (ca. 46% w/w) was coated onto microcrystalline cellulose beads (Cellets® 200) followed by the addition of a taste-masking layer of amino methacrylate copolymer, NF (Eudragit EPO® (EPO)) coating suspension. The efficiency of both the drug coating process and the taste-masking polymer coating process, as well as the taste masking ODTs was determined using potency and drug release analysis. Magnesium stearate was found to be advantageous over talc in improving the efficiency of the EPO coating suspension. A response surface methodology using a Box–Behnken design for the tablets revealed compression force and levels of both disintegrant and talc to be the main factors influencing the ODT properties. Blending of talc to the EPO-coated beads was found to be the most critical factor in ensuring that ODTs disintegrate within 30?s. The optimized ODTs formulation also showed negligible (<0.5%) drug release in 1?min using phosphate buffer, pH 6.8 (which is analogous to the residence time and pH in the oral cavity). By carefully adjusting the levels of coating polymers, the amounts of disintegrant and talc, as well as the compression force, robust ODTs can be obtained to improve pediatric and geriatric patient compliance for clindamycin oral dosage forms.     

Novel taste-masked orally disintegrating tablets for a highly soluble drug with an extremely bitter taste: design rationale and evaluation

The purpose of this study was to evaluate the taste masking potential of novel solid dispersions (SDs) using Eudragit^® EPO as the excipient when incorporated into the orally disintegrating tablets (ODTs) for delivering a highly soluble drug with an extremely bitter taste. The pyridostigmine bromides (PB) SDs (PBSDs) were prepared by solvent evaporation–deposition method. The physicochemical properties of PBSDs were investigated by means of differential scanning calorimetry and Fourier transformed infrared spectroscopy. The dissolution test showed that only about 8% of PB was released from PBSDs in the simulated salivary fluid in 30 s. Therefore, PBSDs were considered taste-masked and selected for formulation of PBODTs. A central composite design was employed for process optimization. Multiple linear regression analysis for process optimization revealed that the optimal PBODTs were obtained, when the microcrystalline cellulose and crospovidone were 17.16 and 5.55 (%, w/w), respectively, and the average in vivo disintegration time was 25 s. The bitterness threshold of PB was examined by a sensory test, and the threshold value was set as 3?mg in each tablet. Taste evaluation of PBODTs in 18 volunteers revealed considerable taste masking with bitterness below the threshold value. PBODTs also revealed rapid drug release (around 99%, 2?min) in the simulated gastric fluid. The mean PB plasma concentration–time profiles of PBODTs and that of the commercial tablets were comparable, with closely similar pattern. Bioequivalence assessment results demonstrated that PBODTs and the commercial tablets were bioequivalent. In conclusion, PBODTs are prepared successfully, with taste masking and rapid disintegration in the oral cavity.     

Considerations in the development of an in vitro dissolution condition for lacidipine tablets: in vivo pharmacokinetic evaluation

In this study, a new discriminative dissolution condition for lacidipine tablets was developed by the established in vitro–in vivo relationship. Series of dissolution media of phosphate buffer solution (PBS) covering the pH range of 1–7.2 and pH 6.8 PBS containing different concentrations of sodium dodecyl sulfate (SDS), were prepared and used to investigate the dissolution behavior of lacidipine tablets. There was an obvious difference in the dissolution profiles of the both brands in pH 6.8 PBS medium containing 0.1% SDS. The pharmacokinetic study of the two lacidipine tablets was carried out in the healthy beagle dogs at a single dose of 4?mg. Statistical comparison of the AUC_0–24, C_max, and T_max showed a significant difference in the two brand tablets, coinciding with the dissolution performance with pH 6.8 PBS containing 0.1% SDS. The superiority of the proposed system, pH 6.8 PBS containing 0.1% SDS, could serve as a dissolution medium for lacidipine tablets, and more important it could discriminate the in vivo pharmacokinetic behavior for different brands of products. In summary, in vivo pharmacokinetic evaluation is essential to develop an appropriate in vitro dissolution condition for oral solid dosage forms of poorly soluble drugs.     

Evaluation of the palatabilities in 10 different famotidine orally disintegrating tablets by combination of disintegration device and taste sensor

The purpose of this study was to evaluate the palatabilities of the original and nine generic versions of famotidine orally disintegrating tablets (FODTs) by means of disintegration times and bitterness intensities determined using in combination disintegration device and taste sensor comparison of human gustatory sensation tests. The disintegration times were determined using a new disintegration testing equipment for ODTs, the OD-mate and bitterness intensities were determined using the SA501C taste-sensing system. The disintegration time and bitterness of each FODT was evaluated in gustatory sensation tests. There was a good correlation between the disintegration times of 10 FODTs estimated in human gustatory testing and those found using the OD-mate. The bitterness intensities of FODTs at 10, 20 and 30?s after starting the disintegration using the OD-mate and the values determined by the taste sensor were highly correlated with the bitterness intensities determined in gustatory sensation testing. A combination of the OD-mate and the SA501C was capable of predicting the palatabilities, disintegration properties and bitterness intensity of FODTs.     

Formulation of olanzapine nanosuspension based orally disintegrating tablets (ODT); comparative evaluation of lyophilization and electrospraying process as solidification techniques

Olanzapine (OLAN) as an antipsychotic agent has shown its potential in effective management of psychotic disorders however its use is limited because of its poor water solubility. The aim of present work was to improve solubility of OLAN by developing a stable nanocrystal based orally disintegrating tablets (ODTs), using hyperomellose as potential stabilizer. Comparative evaluation of electrospraying and lyophilization as solidification techniques was carried out to assess its effect on solid state properties of OLAN nanocrystals before transformation to ODTs.OLAN Nanosuspension was developed using antisolvent precipitation method and exhibited particle size, polydispersity index and zetapotential value of 223.1?±?1.5?nm, 0.105?±?0.4 and ?17.9?±?3.5?mV respectively. Solid powders obtained from both the solidification techniques were compared in terms of size after re-dispersion, particle morphology, surface area, pore volume and solid state of drug present. Subsequently ODTs were prepared from these powders with needful excipients and % amount dissolved was evaluated. Rate of dispersion was found to be higher for ODTs prepared using lyophilized powder (～84% in 5?min) while other characterization parameters were comparatively similar. Overall, Lyophilization resulted in powders with better bulk level properties in comparison to electrospraying process.     

Formulation and evaluation of meloxicam oral disintegrating tablet with dissolution enhanced by combination of cyclodextrin and ion exchange resins

Context: The bitter taste of drug is masked by the exchange of ionized drugs with counter ions of ion exchange resin, forming “resinate”. Cyclodextrin reduces the unpleasant taste and enhances the drug solubility by encapsulating drug molecules into its central cavity.

Objective: Oral disintegrating tablets (ODTs) using the combination of ion exchange resin and cyclodextrin was developed, to mask the bitter taste and enhance drug dissolution.

Methods: Meloxicam (MX) was selected as a model drug. Formulations containing various forms of MX (free drug, MX-loaded resin or resinate, complexes of MX and 2-hydroxypropyl-β-cyclodextrin (HPβCD) or MX/HPβCD complexes, and a mixture of resinate and MX/HPβCD complexes) were made by direct compression. The ODTs were evaluated for weight variation, thickness, diameter, hardness, friability, disintegration time, wetting time, MX content, MX release, degree of bitter taste and stability.

Results and discussion: The tablet hardness was ～3?kg/in², and the friability was <1%. Tablets formulated with resinate and the mixture of resinate and MX/HPβCD complexes disintegrated rapidly within 60?s, which is the acceptable limit for ODTs. These results were corresponded to the in vivo disintegration and wetting times. However, only tablets containing the mixture of resinate and MX/HPβCD complexes provided complete MX dissolution and successfully masked the bitter taste. In addition, this tablet was stable at least 6 months.

Conclusions: The combination of ion exchange resin and cyclodextrin could be used in ODTs to mask the bitter taste and enhance the dissolution of drugs that are weakly soluble in water.     

Effect of the filler grade on the characteristics and the sublingual permeability of atropine sulfate fast disintegrating sublingual tablets

Abstract

Context: AS FDSTs will provide an accessible alternative for AS autoinjector (ATROPEN^®), and a noninvasive first-aid antidote for the treatment of organophosphate (OP) poisoning and reduce the number of fatalities due to nerve gas attacks or OP pesticide poisoning.

Objective: The effects of changing the filler grade on the characteristics of atropine sulfate (AS) fast disintegrating sublingual tablets (FDSTs) and AS sublingual permeability were investigated in order to optimize the formulation of AS FDSTs and, therefore, AS sublingual permeability.

Methods: Two batches of AS FDSTs containing AS 8?mg were formulated and manufactured using two different filler grades: microcrystalline cellulose (MCC) UF-702 (formulation A) and MCC PH-301 (formulation B). Several United States Pharmacopeia (USP) and non-USP physical tests were performed to evaluate the AS FDSTs’ characteristics. The AS permeability from the two AS FDST batches were evaluated using Franz cells through excised porcine sublingual membranes. Results were statistically compared at p?<?.05.

Results: Both batches passed the content uniformity and friability tests. Formulation A tablets were significantly different from formulation A tablets and resulted in better powder flowability, higher breaking force, faster disintegration, faster dissolution rate, higher water uptake, and higher AS permeability.

Conclusion: The selection of the filler grade to be used in the formulation of AS FDSTs can significantly impact their characteristics and significantly affect AS sublingual permeability, which can be used to improve the sublingual delivery of AS and the potential of using AS FDSTs as an alternative dosage form for the first-aid treatment of OP poisoning.     

Formulation and Evaluation of Rapidly Disintegrating Fenoverine Tablets: Effect of Superdisintegrants

The objective of this study was to formulate directly compressible rapidly disintegrating tablets of fenoverine with sufficient mechanical integrity, content uniformity, and acceptable palatability to assist patients of any age group for easy administration. Effect of varying concentrations of different superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate on disintegration time was studied. Tablets were evaluated for weight variation, thickness, hardness, friability, taste, drug content, in vitro and in vivo disintegration time, and in vitro drug release. Other parameters such as wetting time, water absorption ratio (‘R’), and drug-excipient compatibility were also evaluated. The disintegration time of the best rapidly disintegrating tablet formulation among those tested was observed to be 15.9 sec in vitro and 37.16 sec in vivo. Good correlation was observed between disintegration time and ‘R’ for each of the three superdisintegrants at the concentrations studied. Considering the ‘R’ values and disintegration time, crospovidone was significantly superior (p < 0.05) compared to the other superdisintegrants tested. Release of drug was faster from formulations containing 6% crospovidone (CP 6) compared to the marketed fenoverine (Spasmopriv®) capsules. Similarity factor ‘f₂’ (51.5) between dissolution profiles of the rapidly disintegrating tablet formulation CP 6 and the marketed formulation indicated that the two dissolution profiles were similar. Differential scanning calorimetric studies did not indicate any excipient incompatibility, either during mixing or after compression. In conclusion, directly compressible rapidly disintegrating tablets of fenoverine with lower friability, acceptable taste, and shorter disintegration times were obtained using crospovidone and other excipients at optimum concentrations.     

Controlled release of ziprasidone solid dispersion systems from osmotic pump tablets with enhanced bioavailability in the fasted state

Objective: The purpose of this work was to develop a controlled release of ziprasidone with no food effect by the osmotic release strategy.

Methods: The solution of ziprasidone and poloxamer188 (P188) with different weight ratios was spray-dried to form solid dispersion of ziprasidone (SD-ZIP). The SD-ZIP was characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (X-RD) and solubility testing. The SD-ZIP osmotic pump tablets were prepared by wet granulation method. The effect of formulation variables on the release characteristic was investigated. The SD-ZIP osmotic pump tablets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation Zeldox® as a control.

Results: The results of DSC and X-RD indicated that ziprasidone resides in P188 with no crystalline changes. Solubility studies demonstrated that the solubility of SD-ZIP was substantially improved compared to ziprasidone and physical mixtures of ziprasidone and P188. The optimized formulation and drug release profiles of SD-ZIP osmotic pump tablets in different medium were obtained which showed typical osmotically controlled release and could fitted to zero-order kinetics with good linear correlation. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolong actions and no food effect was achieved simultaneously in SD-ZIP osmotic pump tablet compared with Zeldox®.

Conclusion: The SD-ZIP osmotic pump tablet could be able to enhance the bioavailability in the fasted state and showed sustained release with prolonged actions.     

Different trends for preparation of budesonide pellets with enhanced dissolution rate

The current research attempts different approaches to overcome the poor dissolution of budesonide (a poorly water-soluble drug) from pellet formulations. Various methods such as liqui-pellet (LP) and pellets made of solid dispersion (SDP) were employed and compared to conventional pellets (CP). In SDP method, budesonide:PVP solid dispersion was prepared followed by extrusion-pelletization. Solid dispersion of budesonide-PVP was also layered to the surface of placebo pellets (LSDP). In LP technique, budesonide dispersed in PEG 400 was mixed with Avicel or Avicel:lactose and was extruded-spheronized. Pellets were evaluated for their shape, size, mechanical properties and dissolution rate. The pellets made by LSDP method were significantly harder than CP or PSDP. LP with a loading factor greater than 0.34 was very soft compared to CP and SDP. Pelletization of budesonide SD (PSDP) did not have a tremendous effect on the dissolution enhancement of budesonide compared to CP whilst LSDP showed faster drug release. In conclusion, the layering of budesonide solid dispersion on placebo pellets (LSDP) was the most promising approach for the production of pellets with the highest dissolution rate so that more than 80% of the drug was released within the first 5 min. Also this formulation had proper mechanical properties. This method has the capability to overcome the poor dissolution of budesonide associated with the pellet containing Avicel, and could be employed for the dissolution enhancement of other poorly water-soluble drugs in pellet form.     

Preparation of stable micron-sized crystalline irbesartan particles for the enhancement of dissolution rate

Purpose: In this study, micron-sized crystalline drug particles of irbesartan (IBS) were prepared to improve its stability and dissolution rate.

Method: The approach to crystalline particles was based on the liquid precipitation process by which the amorphous particles were prepared. Pharmaceutical acceptable additives were used as the crystallization agent to convert the amorphous drug into crystalline particles. High pressure homogenization (HPH) process has been employed to reduce the size of the crystalline particles, and the micron-sized particles were obtained by the freeze-drying process.

Results: Different additives show different influences on the polymorphic form of IBS. Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) were effective in stabilizing amorphous particles instead of converting amorphous drug into crystalline particles, while poloxamer407 (F127) and tween80 (T80) could convert the amorphous drug into crystalline particles. T80 was also effective in controlling the particle size than that of F127. After HPH, crystalline particles with an average of 0.8 μm were obtained. The freeze-dried micron-sized crystalline particles exhibited significantly enhanced in vitro dissolution rate when compared to the raw drug. SEM, FT-IR, XRD, DSC and dissolution rate studies indicated that the micron-sized particles were stable during 6 months storage.

Conclusion: The preparation of micron-sized crystalline drug particles is an effective way to improve the stability and dissolution rate of irbesartan.     

Effect of batch age on potency and dissolution of levothyroxine sodium tablets: impact of BP and USP monograph differences on dissolution results

Controversies surround levothyroxine sodium as a drug and product, and are reflected in compendia (USP vs BP) differences in levothyroxine sodium tablets specifications concerning potency limit and dissolution test conditions, and in lack of consensus on several issues such as whether the drug BCS class I or III. We have recently published a clinical study in patients comparing the efficacy of multisource 100?mcg levothyroxine sodium tablets (three sources, two brands, a total of five batches). Clinical efficacy and dissolution rate data varied among the tablet batches studied and indicated that brand/source interchangeability could not be claimed. The efficacy parameters showed good correlation with dissolution data generated under BP 2014, but not under USP 2014 dissolution test conditions. In the present study, we decided to expand the number of tablet batches studied in vitro to a total of 12, to report potency and content uniformity data missing in the clinical study, and to further examine the discrepancy in dissolution results based on the medium used. The wide range of batch age in the studied samples allowed investigating the effect of batch age on in-vitro tablet performance parameters. Generated potency values indicated the prevalence of super-potent tablet batches. The dissolution data reflected the effect of compendia monograph differences in dissolution medium. The results also indicated an inverse relationship between tablet potency and batch age and, between dissolution and batch age. The possible effect of potency results on the generated dissolution data was discussed. Statistical significance of correlations examined was assessed by linear and non-linear regression analysis. Statistical significance was evident for the relation between batch age and BP 2014 dissolution data, compared to USP 2014 dissolution results.     

Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold

Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.     

Considerations in the development of an in vitro dissolution condition for lacidipine tablets: in vivo pharmacokinetic evaluation

In this study, a new discriminative dissolution condition for lacidipine tablets was developed by the established in vitro-in vivo relationship. Series of dissolution media of phosphate buffer solution (PBS) covering the pH range of 1-7.2 and pH 6.8 PBS containing different concentrations of sodium dodecyl sulfate (SDS), were prepared and used to investigate the dissolution behavior of lacidipine tablets. There was an obvious difference in the dissolution profiles of the both brands in pH 6.8 PBS medium containing 0.1% SDS. The pharmacokinetic study of the two lacidipine tablets was carried out in the healthy beagle dogs at a single dose of 4 mg. Statistical comparison of the AUC(0-24), C(max), and T(max) showed a significant difference in the two brand tablets, coinciding with the dissolution performance with pH 6.8 PBS containing 0.1% SDS. The superiority of the proposed system, pH 6.8 PBS containing 0.1% SDS, could serve as a dissolution medium for lacidipine tablets, and more important it could discriminate the in vivo pharmacokinetic behavior for different brands of products. In summary, in vivo pharmacokinetic evaluation is essential to develop an appropriate in vitro dissolution condition for oral solid dosage forms of poorly soluble drugs.     

Liesegang Banding for Controlled Size and Growth of Zeolitic‐Imidazolate Frameworks

Here, the formation of periodic precipitation (Liesegang bands) from hybrid (organic–inorganic) components is reported, namely ZIF‐8, ZIF‐67, and their mixed metal derivatives. The spacing and width laws that characterize the Liesegang system are determined and the resulting pattern is exploited to crystal engineer various sizes and doping of the ZIF material. Several key parameters that govern the crystallization process of ZIF‐8 are investigated in each band and the growth of the particles in each band is found to follow an Ostwald ripening mechanism.