Search Results (14)

The purpose of this study was to enhance the stability of montelukast and levocetirizine for the development of a fixed-dose combination (FDC) monolayer tablet. To evaluate the compatibility of montelukast and levocetirizine, a mixture of the two drugs was prepared, and changes in the appearance characteristics and impurity content were observed in a dry oven at 60 °C. Excipients that contributed minimally to impurity increases were selected to minimize drug interactions. Mannitol, microcrystalline cellulose, croscarmellose sodium, hypromellose, and sodium citrate were chosen as excipients, and montelukast–levocetirizine FDC monolayer tablets were prepared by wet granulating the two drugs separately. A separate granulation of montelukast and levocetirizine, along with the addition of sodium citrate as a pH stabilizer, minimized the changes in tablet appearance and impurity levels. The prepared tablets demonstrated release profiles equivalent to those of commercial products in comparative dissolution tests. Subsequent stability testing at 40 ± 2 °C and 75 ± 5% RH for 6 months confirmed that the drug content, dissolution rate, and impurity content met the specified acceptance criteria. In conclusion, the montelukast–levocetirizine FDC monolayer tablet developed in this study offers a potential alternative to commercial products. Full article

The present study aimed to develop 3D printed dosage forms, using custom-made filaments loaded with diclofenac sodium (DS). The printed tablets were developed by implementing a quality by design (QbD) approach. Filaments with adequate FDM 3D printing characteristics were produced via hot melt extrusion (HME). Their formulation included DS as active substance, polyvinyl alcohol (PVA) as a polymer, different types of plasticisers (mannitol, erythritol, isomalt, maltodextrin and PEG) and superdisintegrants (crospovidone and croscarmellose sodium). The physicochemical and mechanical properties of the extruded filaments were investigated through differential scanning calorimetry (DSC), X-ray diffraction (XRD) and tensile measurements. In addition, cylindrical-shaped and tubular-shaped 3D dosage forms were printed, and their dissolution behaviour was assessed via various drug release kinetic models. DSC and XRD results demonstrated the amorphous dispersion of DS into the polymeric filaments. Moreover, the 3D printed tablets, regardless of their composition, exhibited a DS release of nearly 90% after 45 min at pH 6.8, while their release behaviour was effectively described by the Korsmeyer–Peppas model. Notably, the novel tube design, which was anticipated to increase the drug release rate, proved the opposite based on the in vitro dissolution study results. Additionally, the use of crospovidone increased DS release rate, whereas croscarmellose sodium decreased it. Full article

This study aimed to prepare tablets of black pepper extract using the Design of Experiments (DOE) approach. The levels of three factors—compressional force, croscarmellose sodium (CCS), and microcrystalline cellulose (MCC)—were screened using the one-factor-at-a-time technique, followed by the DOE utilizing the Box–Behnken design. The respective variations for each factor were as follows: compressional force (1500–2500 psi), CCS (1–3%), and MCC (32–42%). The results indicated that compressional force significantly decreased tablet thickness and friability, while increasing hardness and prolonging disintegration time. CCS significantly shortened disintegration time but did not affect tablet thickness, hardness, and friability. MCC, on the other hand, significantly increased tablet thickness and hardness, while significantly decreasing friability. Furthermore, the study observed interactions among factors and quadratic effects of each factor, which significantly influenced tablet properties. The optimal tablet formulation consisted of 2.2% CCS, 37% MCC, and a compressional force of 2000 psi. These tablets had a weight of 198.39 ± 0.49 mg, a diameter of 9.67 ± 0.01 mm, a thickness of 1.98 ± 0.02 mm, a hardness of 7.36 ± 0.24 kP, a friability of 0.11 ± 0.02%, and a disintegration time of 5.59 ± 0.39 min. The actual values obtained using the optimal conditions closely matched the predicted values, with a low percent error (less than 5%). In conclusion, the application of the DOE approach successfully developed tablets of black pepper extract, which can be utilized as food supplement products. Full article

Domperidone (DOM) is a drug commonly used to treat nausea and vomiting, as well as gastrointestinal disorders. However, its low solubility and extensive metabolism pose significant administration challenges. In this study, we aimed to improve DOM solubility and avoid its metabolism by developing nanocrystals (NC) of DOM through a 3D printing technology—melting solidification printing process (MESO-PP)—to be delivered via a solid dosage form (SDF) that can be administered sublingually. We obtained DOM-NCs using the wet milling process and designed an ultra-rapid release ink (composed of PEG 1500, propylene glycol, sodium starch glycolate, croscarmellose sodium, and sodium citrate) for the 3D printing process. The results demonstrated an increase in the saturation solubility of DOM in both water and simulated saliva without any physicochemical changes in the ink as observed by DSC, TGA, DRX, and FT-IR. The combination of nanotechnology and 3D printing technology enabled us to produce a rapidly disintegrating SDF with an improved drug-release profile. This study demonstrates the potential of developing sublingual dosage forms for drugs with low aqueous solubility using nanotechnology and 3D printing technology, providing a feasible solution to the challenges associated with the administration of drugs with low solubility and extensive metabolism in pharmacology. Full article

The first and only antidepressant drug on the market with solid proof of clinically significant serotonin and noradrenaline reuptake inhibition is clomipramine (CLP). However, significant first-pass metabolism reduces its absorption to less than 62%. It is heavily protein-bound and broadly dispersed across the body (9–25 L/kg volume of distribution). The purpose of this research was to formulate CLP orodispersible tablets that immediately enable the drug to enter the bloodstream and bypass systemic portal circulation to improve its bioavailability. A factorial design was employed using varied amounts of Plantago ovata mucilage (POM) as a natural superdisintegrant, as well as croscarmellose sodium and crospovidone as synthetic disintegrants. Their physiochemical compatibility was evaluated by FTIR, DSC/TGA, and PXRD analysis. The blend of all formulations was assessed for pre- and post-compaction parameters. The study found that tablets comprising Plantago ovata mucilage as a superdisintegrant showed a rapid in vitro disintegration time, i.e., around 8.39 s, and had an excellent dissolution profile. The anti-depressant efficacy was evaluated by an open-field test (OFT) and the forced swimming test (FST) was applied to create hopelessness and despair behavior as a model of depression in animals (Albino rats). The in vivo study revealed that the efficiency of the optimized formulation (F9) in the treatment of depression is more than the marketed available clomfranil tablet, and may be linked to its rapid disintegration and bypassing of systemic portal circulation. Full article

Pharmaceutical tablet disintegration is a critical process for dissolving and enabling the absorption of the drug substance into the blood stream. The tablet disintegration process consists of multiple connected and interdependent mechanisms: liquid penetration, swelling, dissolution, and break-up. One key dependence is the dynamic change of the pore space in a tablet caused by the swelling of particles while the tablet takes up liquid. This study analysed the changes in the pore structure during disintegration by coupling the discrete element method (DEM) with a single-particle swelling model and experimental liquid penetration data from terahertz-pulsed imaging (TPI). The coupled model is demonstrated and validated for pure microcrystalline cellulose (MCC) tablets across three porosities (10, 15, and 22%) and MCC with three different concentrations of croscarmellose sodium (CCS) (2, 5, and 8% w/w). The model was validated using experimental tablet swelling from TPI. The model captured the difference in the swelling behaviour of tablets with different porosities and formulations well. Both the experimental and modelling results showed that the swelling was lowest (i.e., time to reach the maximum normalised swelling capacity) for tablets with the highest CCS concentration, $c_{\mathrm{CCS}}$ = 8%. The simulations revealed that this was caused by the closure of the pores in both the wetted volume and dry volume of the tablet. The closure of the pores hinders the liquid from accessing other particles and slows down the overall swelling process. This study provides new insights into the changes in the pore space during disintegration, which is crucial to better understand the impact of porosity and formulations on the performance of tablets. Full article

Telmisartan (Tel) is a potent antihypertensive drug with a very poor aqueous solubility, especially in pH ranging from 3 to 9 (i.e., biological fluids) that results in poor bioavailability. Our aim was to improve Tel solubility and dissolution rates without the need for expensive multistep procedures, and without inclusion of alkalinizers. This study adopted the use of surface solid dispersions (SSDs) employing superdisintegrants, hydrophilic polymers and combined carriers including a superdisintegrant with a hydrophilic polymer. Tel-SSDs were formulated using thesolvent evaporation method. Compatibility between Tel and different carriers was examined via FT-IR. Tel-SSDs were evaluated optically and thermally to reveal a complete loss of the crystalline nature of the drug. Both drug content and percentage yield were calculated to judge the efficiency of the preparation technique used. Saturation, aqueous solubility, and dissolutions rates were determined. Dissolution profiles were studied using model dependent and independent approaches and were subjected to the pair-wise procedure using the DDsolver software program. Effect of aging was studied by comparing the drug content and dissolution profiles of freshly prepared SSDs with aged samples. All Tel-SSDs showed acceptable physical properties. Tel-SSDs showed pertinent enhancement related to the carrier used. Combined surface solid dispersions employing superdisintegrant croscarmellose sodium with either hydrophilic polymer PEG 4000 or Poloxamer 407 gave remarkable enhancement in solubility and dissolution rates of Tel where more than 90% of the drug was released within 20 min. The effect of aging results proved a non-significant difference in the drug content and dissolution profiles between fresh and aged samples. Formulation of Tel SSDs using combined carriers proved to be effective in enhancing the aqueous solubility and dissolution rates of Tel, as well as showing good stability upon aging. Full article

Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug’s bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis. Full article

The symptoms of some diseases show circadian rhythms, such as the morning stiffness associated with pain at the time of awakening in rheumatoid arthritis. Therapy for such diseases doesn’t require immediate release or sustained release of medicament. In such therapies, pulsatile drug release is more suitable with a programmed drug release. The purpose of this research was to formulate press-coated aceclofenac tablets for pulsatile drug delivery with a distinct delay time of no drug release and release of the drug when it is more likely desired (i.e., after 5 to 6 h). Immediate release core tablets having aceclofenac were formulated. Three formulations, F1, F2, and F3, were prepared with variable concentrations of sodium croscarmellose. Pre- and post-compression tests were performed on the core tablets. The selection criteria included the lowest disintegration time as a requirement of pulsatile drug delivery with an immediate release core and a delayed release coat. The disintegration times of F1, F2, and F3 were 120 s, 60 s, and 15 s, respectively. Therefore, the F3 formulation was selected as the core tablet formulation because it had the shortest disintegration time (15 s). The core tablets were press-coated using different polymers, such as HPMC K100M, Eudragit L100, HEC, and HPMC E5. The polymers were used in the coatings to hinder the release of the core for the desired time. 36 formulations of polymer were prepared: A1 to A10 had HPMC K100M and Avicel PH102; formulations B1 to B6 had HPMC K100M, Eudragit L100, and Avicel PH102; formulations C1 to C7 had HPMC K100M and hydroxyethyl cellulose; formulations D1 to D7 had HPMC K100M and HPMC E5; and formulations E1 to E6 had changed the coating weight of the formulation used for D6 (having HPMC K100M and HPMC E5 in the ratio of 12.5% to 87.5%). Evaluations of the press-coated tablets were carried out through thickness, hardness, weight variation, friability, and in vitro dissolution tests. These parameters concluded that the formulation of E6, having HPMC K100M and HPMC E5 in the ratio of 12.5% to 87.5% at 600 mg weight, was the most optimum formulation as it showed 3.5% drug release after 4 h, 21.4% drug release after 5 h, and 99.27% drug release after 6 h. Full article

The ColoPulse coating is a pH-dependent coating that can be used to target drug release to the ileo-colonic region. ColoPulse coated tablets and capsules have demonstrated their targeting capabilities in vivo in more than 100 volunteers and patients. However, so far the ColoPulse coating has not been used for multi-particulate pellet formulations. The sulfasalazine–caffeine method can be used to confirm ileo-colonic drug delivery in vivo. Caffeine serves as a release marker in this method, while sulfasalazine serves as a marker for colonic arrival. In this study, extrusion–spheronization was used to produce microcrystalline cellulose based pellets containing both caffeine and sulfasalazine. Dissolution tests revealed that a superdisintegrant, i.e., croscarmellose sodium or sodium starch glycolate, should be incorporated in the formulation to achieve acceptable release profiles for both sulfasalazine and caffeine. However, acceptable release profiles were only obtained when the pelletizing liquid consisted of ethanol/water 1/1 (v/v) but not with pure water. This phenomenon was ascribed to the differences in the degree of swelling of the superdisintegrant in the pelletizing liquid during the granulation process. The pellets were coated with the ColoPulse coating and showed the desired pH-dependent pulsatile release profile in vitro. In future clinical studies, ileo-colonic targeting should be verified. Full article

Isoflavones can be found in different chemical forms, but the health beneficial effects mainly appear in their free forms—aglycones. Their yield in red clover (Trifolium pratensis L.) extracts differs due to different extraction and hydrolysis methodologies. The main aim of this study was to obtain the highest yields of daidzein and genistein from red clover blossoms through the various extraction and hydrolysis methods and to increase their quantities using additional excipients. Extracts were obtained by ultrasound-assisted, heat-reflux and maceration methods combining them with acidic, alkaline, and thermal hydrolysis. Using ultrasound-assisted extraction with optimal conditions and heat-reflux method highest yields of isoflavones were obtained in UTE510 (393.23 ± 19.66 µg/g daidzein and 171.57 ± 8.58 µg/g genistein); UTE530 (415.07 ± 20.75 µg/g daidzein and 150.57 ± 7.53 µg/g genistein) and HNE5 (432.30 ± 21.61 µg/g daidzein and 154.50 ± 7.72 µg/g genistein) samples. These conditions were used with excipients: magnesium aluminometasilicate, croscarmellose sodium, sodium carboxymethyl starch and vinylpyrrolidone-vinyl acetate copolymer. This is the first study reporting the ability of the vinylpyrrolidone-vinyl acetate copolymer to promote solubilization and availability of active compounds from a herbal extract, resulting in enhanced isoflavones yield. The results of the present study showing increased solubility and availability provided by the vinylpyrrolidone-vinyl acetate copolymer suggest that this preparation could in principle also reduce variability due to limited water solubility of isoflavones. Full article

The conventional “top-down”, “bottom-up” and “combination” approaches of generating drug nanocrystals produce a “nanosuspension” (NS). It requires significant downstream processing for drying the liquid by suitable means followed by its granulation to develop an oral solid dosage form (OSD). In this paper, we used a novel, spray drying-based NanoCrySP technology for the generation of drug nanocrystals in the form of nanocrystalline solid dispersion (NCSD). We hypothesized that the NCSD would require minimal downstream processing since the nanocrystals are obtained in powder form during spray drying. We further compared downstream processing of NS and NCSD of diclofenac acid (DCF) prepared by wet media milling and NanoCrySP technology, respectively. The NS and NCSD were characterized for crystallinity, crystal size, assay and dissolution. The NCSD was physically mixed with 0.3% Aerosil^® 200, 1.76% croscarmellose sodium (CCS) and 0.4% sodium stearyl fumarate (SSF) and filled into size 0 hard gelatin capsules. The NS was first wet granulated using Pearlitol^® SD 200 (G1 granules) and Celphere^® 203 (G2 granules) in a fluidized bed processor, and the resulting granules were mixed using the same extra granular excipients as NCSD and filled into capsules. A discriminatory dissolution method was developed to monitor changes in dissolution behavior due to crystal growth during processing. Cost analysis and comparison of process efficiency was performed using an innovation radar tool. The NS and NCSD were successfully fabricated with a crystal size of 363 ± 21.87 and 361.61 ± 11.78, respectively. In comparison to NCSD-based capsules (65.13%), the G1 and G2 granules showed crystal growth and decrease in dissolution to 52.68% and 48.37%, respectively, in 120 min. The overall cost for downstream processing of NCSD was up to 80% lower than that of NS. An innovation radar tool also concluded that the one-step NanoCrySP technology was more efficient and required less downstream processing than the two-step wet media milling approach for conversion of nanocrystals to OSD. Full article

This study aimed to design phosphatidylcholine (PC)-based solid dispersion (SD) systems for enhancing the apparent aqueous solubility and dissolution of celecoxib (CLC), a selective cyclooxygenase-2 inhibitor with a highly hydrophobic property. Although PC-based dispersion formulations considerably increased solubilities of CLC, the lipidic texture of PC was not appropriate as a solid dosage form for oral administration of CLC. To mask the lipidic texture of PC-based matrices, Neusilin^® US2, an adsorbent material with a porous structure and large surface area widely used in the pharmaceutical industry, was employed and thereby fully powderized PC-based dispersion formulations could be fabricated. However, PC matrices containing CLC strongly adsorbed to the pores of Neusilin^® US2 was not able to be rapidly released. To address this problem, different hydrophilic materials were examined to promote the release of the CLC-dispersed PC matrices from Neusilin^® US2. Among tested hydrophilic materials, croscarmellose sodium was the most suitable to facilitate fast drug dissolution from Neusilin^® US2 particles, showing significantly enhanced apparent aqueous solubility and dissolution behavior of CLC. Through differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy (FT-IR) analysis, a considerably reduced crystallinity of CLC dispersed in the PC-based dispersion formulations was demonstrated. The PC-based SD formulations developed in this study would be useful for improving the oral bioavailability of poorly soluble drugs such as CLC. Full article

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor, primarily used for the treatment of hypertension, congestive heart failure, and heart attack. It belongs to BCS class III having a half-life of 12 hrs and 25% bioavailability. The purpose of the present work was to develop a press-coated, floating-pulsatile drug delivery system. The core tablet was formulated using the super-disintegrants crosprovidone and croscarmellose sodium. A press-coated tablet (barrier layer) contained the polymer carrageenan, xanthan gum, HPMC K4M, and HPMC K15M. The buoyant layer was optimized with HPMC K100M, sodium bicarbonate, and citric acid. The tablets were evaluated for physical characteristics, floating lag time, swelling index, FTIR, DSC, and in vitro and in vivo behavior. The 5% superdisintgrant showed good results. The FTIR and DSC study predicted no chemical interactions between the drug and excipients. The formulation containing xanthan gum showed drug retaining abilities, but failed to float. The tablet containing HPMC K15M showed a high swelling index. The lag time for the tablet coated with 200 mg carrageenan was 3±0.1 hrs with 99.99±1.5% drug release; with 140 mg HPMC K4M, the lag time was 3±0.1 hrs with 99.71±1.2% drug release; and with 120 mg HPMC K15M, the lag time was 3±0.2 hrs with 99.98±1.7% drug release. The release mechanism of the tablet followed the Korsmeyer-Peppas equation and a first-order release pattern. Floating and lag time behavior have shown good in vitro and in vivo correlations. Full article