Amorphous State In Solid Dispersion Research Articles

Formulation and Evaluation of Ledipasvir Nano-suspension Through QbD Approach

Ledipasvir, belonging to the BCS class II, is a directly acting anti-viral agent used to treat Hepatitis C virus infections. Due to poor water solubility and oral bioavailability, developing an effective delivery system for this drug has been an enormously challenging issue for the formulators. Moreover, suitable dosage forms for pediatric and geriatric patients and patients having difficulty in swallowing as well pose an added burden. Therefore, the present study aims to formulate a nanosuspension, via a solid dispersion technique, based on liquid oral suspension using the Quality by Design (QbD) method. Primarily, the compatible polymers for Ledipasvir were screened using FT-IR and DSC, and finally, the polymers- poloxamer 188, poloxamer 407, HPC and HMPC were selected, considering their ability to turn the API into amorphous state in solid dispersions. The design of formulation and analysis with the D-Optimal design using Design Expert® Software revealed that poloxamer 188 and poloxamer 407 at 0.3:0.7 ratio of Ledipasvir:Polymer produced the optimized nanosuspension formulations with a statistically significant mathematical model. Subsequently, the formulations were stabilized using a suspension vehicle optimized via Box-Behnken design using the amount of xanthan gum (gm), avicel® RC-591 (gm) and citric acid monohydrate (gm) as independent variables, and viscosity (cp) and zeta potential (mv) as responses. The dissolution profiles revealed that the prepared suspensions of Ledipasvir had much faster dissolution than the market products available as the tablet dosage form. In-vivo simulation studies using PKSolver® suggested that the absorption of the drug from the formulated suspensions was comparable to that of market product up to a single dose level (90 mg) and superseded in triplicate dose level (270 mg). The formulated suspensions were found to be stable over three- and six-month periods, as identified via accelerated stability studies. Interestingly, the dissolution profile of the stabilized suspensions was found to be similar after six months to that of the initial. Dhaka Univ. J. Pharm. Sci. 22(2): 173-188, 2023 (December)

ENHANCEMENT OF SOLUBILITY OF POORLY SOLUBLE DRUG LANSOPRAZOLE

Objective: To improve the solubility of lansoprazole with solid dispersion (SD) method by using hydrophilic polymer PEG 6000, PEG 15000 and amphiphilic polymer solupus. Methods: Solid dispersions of lansoprazole were prepared with polymers PEG 6000, PEG 15000 and amphiphilic polymer soluplus, using three methods of preparation–1) solvent melting 2) solvent evaporation and 3) microwave heating method along with different drug: carrier ratios. Performance of the prepared formulations were evaluated for solubility, fourier transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC) parameters. Results: All SDs showed enhancement in solubility of lansoprazole. Solubility and also carrier concentration showed a positive effect on solubility. The lansoprazole-soluplus solid dispersion 1:3 in concentration showed enhanced aqueous solubility when formulated with a solvent melting procedure. Conclusion: The studies indicated that PEG 6000, PEG 15000 and Soluplus inhibite crystallization of lansoprazole, subsequently form amorphous state in solid dispersion, which is, confirmed via FTIR and DSC results of lansoprazole solid dispersion.

Nano-sized Solid Dispersions for Improving the Bioavailability of Poorly Water-soluble Drugs.

It has been well established that solid dispersions have a high potential to increase the release rate of poorly water-soluble drugs, resulting in high drug bioavailability. Solid dispersions have been vigorously investigated with various practical approaches in recent decades. Improvements in wettability, molecular interactions and drugs being held in an amorphous state in solid dispersions are the main mechanisms underlying the high drug release rate. Moreover, the synergistic effect of incorporating nanotechnology in solid dispersions is expected to lead to an advanced drug delivery system for poorly water-soluble drugs. However, to date, there is still a lack of reviews providing outlooks on the nano-sized solid dispersions that have been substantially investigated for improving the bioavailability of poorly water-soluble drugs. In the current review, we aim to overview key advantages and approaches for producing nano-sized solid dispersions. The classification of key strategies in developing nano-sized solid dispersions will advance the creation of even more efficient solid dispersions, which will translate into clinical studies.

Quality evaluation and relative bioavailability investigation on three alkaloids of Corydalis saxicola bunting extract in solid dispersion

Corydalis saxicola Bunting, also named Yanhuanglian in China, is widely used in folk prescriptions to treat hepatitis, hepatocirrhosis and hepatic cancer. Its active components consists mainly of alkaloids, which have poor solubility in water. The previous study showed that the absolute bioavailabilities (BA) of the alkaloids were only about 10% after oral administration to rats, compared to intravenous administration. In this paper, the solid dispersion (SD) method was used to improve the BAs of dehydrocavidine (YHL-1), coptisine (YHL-2), and dehydroapocavidine (YHL-3), the main alkaloids of the extract of Corydalis saxicola Bunting, by improving their solubility. The results showed that using PEG 4000 as a carrier at an amount equivalent to 7 folds of the extract could significantly improve the solubility of the compounds in water, pH 1.2 HCl and pH 7.2 PBS. DSC and X-ray detection indicated that the drug might be in a dissolved or amorphous state in SD, which was different from that in the physical mixture. The formulation was further studied in terms of BA enhancement by cumulative urinary excretion after oral administration to rats. A new method using high performance liquid chromatography (HPLC) coupled to a diode-array detector (DAD) was established. The results showed that the relative BAs (RE BAs) of YHL-1, YHL-2 and YHL-3 were all significantly improved by about 1 fold after oral administration of SD solution, compared to the extract suspension (p < 0.05).

Improved Oral Absorption of Poorly Soluble Curcumin via the Concomitant Use of Borneol.

In this study, borneol, a natural active compound was applied to improve the bioavailability of curcumin (CUR). In order to increase CUR solubility and dissolution, solid dispersions (SDs) were prepared with the matrix of polyvinylpyrrolidone (PVP) at various ratios by solvent evaporation method. CUR was evidenced to exist as amorphous state in solid dispersion by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Fourier-transform infrared spectroscopy (FT-IR) was utilized to confirm intermolecular hydrogen bonding. The SD at the ratio of 1:3 (CUR:PVP) exhibited the optimal solubility and dissolution rate in various media. The results of ex vivo permeability studies by everted gut sac method showed that the apparent permeability coefficients (Papp) of CUR in SD across the duodenum, jejunum, and ileum had been significantly improved by co-incubation of borneol, and the improvement degree relied on the concentration of borneol. The pharmacokinetic results in rats indicated that the AUC0-t of CUR-SD (40mg/kg) co-administration of borneol (90mg/kg) were 2.53-fold higher than CUR-SD alone, and 19.41-fold higher than pure CUR (200mg/kg) with borneol (90mg/kg). Therefore, the combination of borneol and solid dispersion strategy provide a potential approach to enhance the oral bioavailability of CUR.

Preparation, optimisation, and in vitro–in vivo evaluation of febuxostat ternary solid dispersion

The research aimed to prepare febuxostat (FEB) solid dispersion through solvent evaporation. Optimised solid dispersion composed of FEB, polyvinylpyrrolidone (PVP K30) and poloxamer at a ratio of 1:3:3 was characterised. Powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) indicated FEB was transformed from crystalline into the amorphous state in solid dispersion and scanning electron microscopy (SEM) revealed the morphology. Fourier transform infrared spectroscopy (FT-IR) suggested the interactions formed between FEB and polymers. A remarkable increase was observed of the optimised formulation in saturation solubility, dissolution studies (96.17 ± 0.79% in pH 6.0), and bioavailability (Cmax 18.25 ± 2.44 vs. 7.72 ± 0.48 μg/mL and AUC0–∞ 53.62 ± 7.63 vs. 34.76 ± 2.45 μg·h/mL). Besides, the FEB solid dispersion showed great stability after 90 days storage. Thus, the present study supports the rationality of PVP K30 and poloxamer188 as co-carriers for the preparation of FEB solid dispersion.

DEVELOPMENT AND EVALUATION OF MONOLITHIC OSMOTIC TABLET OF KETOPROFEN: USING SOLID DISPERSION TECHNIQUE

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The aim of the present study was to develop and evaluate the monolithic osmotic tablet (MOT) composed of the solid dispersion of ketoprofen (KETO), a poorly water-soluble drug. Solid dispersion technique is generally used for immediate release, as this maximizes the amount of drug absorbed. Sustained release may be obtained by combining solid dispersion technique with MOT so as to increase the therapy efficacy and patient compliance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Solid dispersion of KETO was prepared by using solvent melt method with polyethylene glycol (PEG) 6000, a hydrophilic carrier. The ratio of KETO to PEG 6000 were 1:1, 1:3 and 1:5 (%w/w). These solid dispersions were characterized by differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA) and powder X-ray diffraction (PXRD) to ascertain whether there were any physicochemical interactions between drug and carrier.&lt;/p&gt;&lt;p&gt;The tablet core was prepared by using Polyox N80 (a suspending agent), sodium chloride (an osmotic agent), a solid dispersion consisting of PEG 6000 and KETO followed by a coating of cellulose acetate to make the monolithic osmotic tablet.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The results of DSC and PXRD indicated that the drug was in the amorphous state in solid dispersion when PEG 6000 was used as a carrier. The dissolution rate of the solid dispersion was much faster than those for the corresponding physical mixture and pure drug. The optimized MOT formulations were able to deliver KETO at the constant zero order release, above 95% &lt;em&gt;in vitro&lt;/em&gt;, independent to environmental media and stirring rate. The release rate of KETO in the MOT is controlled by osmotic pressure, suspending agent and drug solubility in solid dispersion.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The monolithic osmotic tablet containing solid dispersion has great potential in the controlled delivery of ketoprofen, a water-insoluble drug.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Keywords: &lt;/strong&gt;Ketoprofen, Monolithic osmotic tablet, Solid dispersion, Water insoluble&lt;/p&gt;

Characterization and Pharmacokinetic Study of Aprepitant Solid Dispersions with Soluplus®.

Solid dispersions are a useful approach to improve the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble aprepitant by preparation of solid dispersions. The solid dispersions were characterized by dissolution, FTIR, XRPD, DSC, SEM and pharmacokinetic studies in rats. The dissolution rate of the aprepitant was significantly increased by solid dispersions, and XRD, DSC, and SEM analysis indicated that the aprepitant existed in an amorphous form within the solid dispersions. The result of dissolution study showed that the dissolution rate of SDs was nearly five-fold faster than aprepitant. FTIR spectrometry suggested the presence of intermolecular hydrogen bonds between the aprepitant and polymer. Pharmacokinetic studies in rats indicated that the degree drug absorption was comparable with that of Emend®. Aprepitant exists in an amorphous state in solid dispersions and the solid dispersions can markedly improve the dissolution and oral bioavailability of the aprepitant. The AUC0–t of the SDs was 2.4-fold that of the aprepitant. In addition, the method and its associated techniques are very easy to carry out.

Physicochemical characterization of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions, and finasteride: β-cyclodextrin inclusion complexes

Finasteride is a practically insoluble in water drug that belongs to the Class II of the BCS (poor solubility and high permeability). Solid dispersions are solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. Solid dispersions are a successful strategy to improve drug release of poorly water-soluble drugs such as finasteride. Natural cyclodextrins are doughnut-shaped molecules with an internal hydrophobic cavity and a hydrophilic external surface. The lipophilic cavity enables cyclodextrins to form non-covalent inclusion complexes with a wide variety of poorly water-soluble drugs such as finasteride. The aim of this study was to investigate the formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:β-cyclodextrin inclusion complexes by solvent evaporation method using a mixture of water:ethanol (1:1). The formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:β-cyclodextrin inclusion complexes was investigated and characterized by differential scanning calorimetry (DSC), infrared (IR) spectroscopy, and dissolution studies from capsules containing a quantity equivalent to 5 mg of finasteride. The DSC thermograms revealed the transformation of finasteride into the amorphous state in solid dispersions with PEG 6000 and Kollidon K25, and in inclusion complexes with β-cyclodextrin. The IR spectra demonstrated molecular interaction in solid dispersions of finasteride with PEG 6000, and in inclusion complexes with β-cyclodextrin. Dissolution rate of solid dispersions and inclusion complexes was significantly greater than that of corresponding physical mixtures and pure drug, indicating that the formation of solid dispersions and inclusion complexes increased the solubility of the poorly soluble drug, finasteride.

Effect of Characteristics of Compounds on Maintenance of an Amorphous State in Solid Dispersion with Crospovidone

Solid dispersion (SD) of indomethacin with crospovidone (CrosPVP) shows useful characteristics for preparation of dosage forms. This study aimed to determine the types of drugs that could adopt a stable amorphous form in SD. Twenty compounds with various melting points (70–218°C), molecular weights (135–504) and functional groups (amide, amino, carbonyl, hydroxyl, ketone etc.) were prepared in SD with CrosPVP. The CrosPVP SDs were prepared using a mechanical mixing and heating method. Melting point and molecular weight were found to have no influence on the ability of a compound to maintain an amorphous state in SD. All compounds containing hydrogen‐bond‐donor functional groups existed in an amorphous state in SD for at least 6 months. Infrared spectra suggested an interaction between the functional groups of these compounds and amide carbonyl group of CrosPVP. Compounds without hydrogen‐bond‐donor groups could not maintain an amorphous state and underwent recrystallization within 1 month. It was suggested that the presence of a hydrogen‐bond‐donor functional group in a compound is an important factor affecting the stable formation of SD with CrosPVP, which contains a hydrogen‐bond acceptor.

Dissolution and Bioavailability of Phenobarbital in Solid Dispersion with Phosphatidylcholine.

The dissolution of phenobarbital (PB) from solid dispersion with phosphatidylcholine (PC) was studied. PB was present in an amorphous state in solid dispersion (PB-PC) if the mole fraction of PB was under 0.75. Thus, supersaturation was observed when an excess amount of PB-PC was dispersed in pH 1.2 and 6.8 media. The degree of supersaturation was largest when the mole fraction of PB was 0.25, although it was only 1.3-fold of the PB solubility in this case. Dissolution from PB-PC was rapid and complete in both pH 1.2 and 6.8 media regardless of the mole fraction of PB, above 90% within 5 min. Bioavailability after the oral administration of PB-PC to rabbits with a dose of 15 mg/kg equivalent to PB was compared with that of PB crystals. The area under the plasma concentration curve was bigger, but not significant. The maximum concentration was significantly higher, and the time to maximum concentration was significantly faster. These results indicate that the absorption rate became high with PB-PC because the dissolution was rapid.

Physicochemical properties of phenobarbital solid dispersion with phosphatidylcholine.

We prepared a phenobarbital (PB) solid dispersion (SD) with phosphatidylcholine (PC). PB was present in an amorphous state in SD if its mole fraction was under 0.75. An infrared (IR) spectra study suggested a hydrogen bond between NH in PB and phosphate in PC, with a ratio of about 1:1. When the mole fraction of PB was less than 0.50, differential scanning calorimetry (DSC) curves showed endothermic peaks at 57, 90 and 145 degrees C, and an exothermic peak at 60 degrees C. The IR spectrum and X-ray diffraction pattern changed after holding at 70 degrees C, so at this point it is considered that the metastable state of SD changed into a stable state, and extra energy was released. When the mole fraction of PB was high, PB also arranged near hydrophobic group because an endothermic peak was observed at 46-52 degrees C, which was lower than fully hydrated PC. PB is similar to indomethacin (IM) in molecular shape and to phenytoin (PHT) in chemical structure. Its DSC curve and IR spectra are similar to PHT, and the limit ratio of its amorphous state is the same as IM. It is considered that the chemical structure is an important factor in its interaction to PC, and also, the molecular shape is important to arrange into PC lattice.

Dissolution and bioavailability of phenytoin in solid dispersion with phosphatidylcholine.

An attempt was made to improve the dissolution behavior of phenytoin (PHT), a poorly watersoluble drug, with phosphatidylcholine (PC) solid dispersion (SD). The powder X-ray diffraction patterns indicated that PHT was present in an amorphous state in SD when the molar fraction of PHT was under 0.33. Infrared spectra suggested a weak interaction, probably hydrogen bonding, between PC and PHT in SD. The solubility of PHT was 30μg/ml in both pH1.2 and 6.8 test solutions. The PHT concentration increased temporarily to 36μg/ml in both pH 1.2 and 6.8 test solutions with SD in which the molar fraction of PHT was 0.25 (SD (0.25)). This is only 1.2 times the PHT solubility, but the dissolution rate in pH 1.2 test solution was significantly improved: the PHT concentration reached 24μg/ml in the first 5min, whereas it was 6μg/ml in the case of PHT crystals. The dissolution rate was slightly higher even with physical mixture (PM) because of improved wettability.After oral administration of SD (0.25) to rabbits, plasma concentrations up to 8h were significantly higher than those in the cases of PM (0.25) and PHT crystals, but there was no significant difference in the area under the plasma concentration curve. PM (0.25) did not show improved bioavailability. These results were consistent with the results of the dissolution test at pH1.2. PM gave an increased plasma concentration of PHT if PC was used in a large excess over PHT (PM (0.10)), it was considered that PC functioned as an oil in this case.