Paddle Method Research Articles

Elucidating the particle size effect of andrographolide suspensions on their IVIVC performance in oral absorption

The study aimed to explore the size effect on the in vitro-in vivo correlation (IVIVC) in the oral absorption of andrographolide nanosuspensions (Ag-NS). Ag-NS with controllable particle sizes were prepared by ultrasonic dispersion method, and the formulation and process parameters were optimized through single factor experiments using mean particle size, polydispersity index, and stability as evaluation indicators. The morphology of Ag-NS was observed by scanning electron microscopy (SEM), and the crystalline state of the nanosuspensions was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The dissolution tests were carried out with the paddle method in two different mediums simulating the pH conditions in intestinal fluid (pH 6.8) and gastric fluid (pH 1.2), respectively. The pharmacokinetic behaviors were investigated in rats after oral administration, and a deconvolution approach was introduced to determine the correlation between in vitro dissolution and in vivo absorption (IVIVC). The formulation with the use of lecithin and PEG-800 as stabilizers showed its potential in the size-controllable preparation of Ag-NS. Via altering the ultrasonication amplitude and time, three Ag-NS suspensions with three particle sizes, i.e., Ag-NS 250 (249.8 ± 1.3 nm), Ag-NS 450 (485.2 ± 3.7 nm), Ag-NS 1000 (1015 ± 36.1 nm) were prepared. Their morphological and crystal characteristics were not changed during the size reduction process, but both of their in vitro dissolution and in vivo absorption were improved. Relatively better IVIVC performance was observed with the in vitro dissolution data at pH 6.8 (r > 0.9). With the reduction of particle size, the in vivo absorption fraction was more closed to the level of the in vitro dissolution. In conclusion, the decrease in particle size would improve the dissolution and absorption of Ag-NS, and also affect their IVIVC performance. The study would facilitate the design and quality control of Ag-NS in terms of particle size and dissolution specifications.

Exploring the Scientific Rationality of the Phenomenon of “Different Dosage Forms of the Same Prescription” of Chinese Proprietary Medicine Based on Biopharmaceutical Properties of Powder and Pill of Chuanxiong Chatiao Prescription

Background: The 2020 edition of the Pharmacopoeia of the People’s Republic of China (Chinese Pharmacopoeia 2020 edition) has 255 Chinese prescriptions with different dosage forms, accounting for 21.09% of the total prescriptions (1,209) in Chinese Pharmacopoeia 2020 edition. However, the scientific rationality of the phenomenon of “Different Dosage Forms of the Same Prescription” of Chinese proprietary medicine has been less explored. Based on the dosage form theory of “components in pills release slowly and take effect in slow-acting manner, while in powders release quickly and take effect in fast-acting way,” we provided the in vitro dissolution experiment and in vivo pharmacokinetics of Chuanxiong Chatiao powders and pills in order to rationalize the phenomenon of “Different Dosage Forms of the Same Prescription” of Chuanxiong Chatiao prescription. Materials and Methods: Chuanxiong Chatiao powders and pills were prepared in the laboratory referring to the preparation methods in the Chinese Pharmacopoeia 2020 edition, and the contents of tetramethylpyrazine, ferulic acid, nodakenin, and isoimperatorin were determined by the external standard method. We measured the in vitro dissolution of four analytes of Chuanxiong Chatiao powders and pills according to the second method for dissolution determination (paddle method) in the Chinese Pharmacopoeia 2020 edition, and their corresponding contents in each sampling point were determined by LC-MS/MS. We also provided a pharmacokinetic study of Chuanxiong Chatiao powders and pills. Six female domestic rabbits were divided into two groups (powder and pill groups) and given Chuanxiong Chatiao powders and pills (9.85 g/kg) by surgical administration separately. Blood samples were collected at 5, 15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, 720, and 1,440 min after drug administration to measure the plasma concentration of the four analytes by LC-MS/MS. Results: The results of in vitro dissolution experiment showed that the dissolution rate of four analytes in the powder group was greater than that of the pill group. However, the solubilities of tetramethylpyrazine and isoimperatorin were very low in the powder and pill, which may be related to their low solubility properties. The results of the in vivo pharmacokinetic study of Chuanxiong Chatiao powders and pills showed that T max (h) of ferulic acid and nodakenin in the powder group was 0.420 and 0.053 times that of the pill group and t 1/2 (h) of ferulic acid, nodakenin, and isoimperatorin of the powder group was 0.910, 0.262, and 0.661 times that of the pill group, respectively. Conclusion: The in vitro dissolution rate and in vivo pharmacokinetic parameters of four analytes in CXCTF could partly explain the scientific rationality of the classic theory of “丸者缓也, 散者散也” as in Chinese, which is helpful for providing a basis for the comparison of subsequent dosage forms. The results of our studies also suggest the complexity of the design of dosage forms of Chinese proprietary medicines and imply that we should pay more attention to the scientific rationality of the phenomenon of “Different Dosage Forms of the Same Prescription.”

Formulation of Ebastine Fast-Disintegrating Tablet Using Coprocessed Superdisintegrants and Evaluation of Quality Control Parameters.

Ebastine is a long-acting, nonsedating, second-generation antihistaminic drug that prevents histamine action, mainly in immediate hypersensitivity. This project was aimed to formulate and characterize orodispersible tablets of ebastine, utilizing different proportions of three disintegrants, namely crospovidone, sodium starch glycolate, and coprocessed superdisintegrant. Initially, fifteen trial batches of ebastine orodispersible tablets were outlined using the central composite design of Minitab software. The tablets were formulated by the direct compression method. The compressed tablets were then evaluated for precompression and postcompression physicochemical parameters, such as angle of repose, Carr's index, Hausner's ratio, hardness, thickness, weight variation, drug content, friability, wetting time, disintegration time, dispersion time, and water absorption ratio. The in vitro dissolution test was conducted according to Indian Pharmacopeia 2018, with the help of the rotating paddle method using 0.5% w/v sodium lauryl sulfate buffer in 0.1 N HCl. For the optimized batch (8th batch), all the physicochemical parameters like angle of repose (33.77°), Carr's index (19.34%), Hausner's ratio (1.24), weight variation (202.5 mg), hardness (4.3 kg/cm2), friability (0.44%), thickness (3.16 mm), dissolution (95.78%), and drug content (101.67%) were within the acceptable limit as per Indian Pharmacopeia 2018. The wetting time, disintegration time, dispersion time, and water absorption ratio were reported to be 25.1 seconds, 16.0 seconds, 38.6 seconds, and 91.92%, respectively. Hence, the results suggested that orodispersible tablets of ebastine can be formulated. Furthermore, the mixing of crospovidone, sodium starch glycolate, and coprocessed super disintegrants can result in excellent desirable properties in the orodispersible tablet.

The Study of Cyclosporin A Nanocrystals Uptake and Transport across an Intestinal Epithelial Cell Model.

Cyclosporin A nanocrystals (CsA-NCs) interaction with Caco-2 cells were investigated in this study, including cellular uptake and transport across Caco-2 cell monolayers. CsA-NCs of 165 nm, 240 nm and 450 nm were formulated. The dissolution of CsA-NCs was investigated by paddle method. The effect of size, concentration and incubation time on cellular uptake and dissolution kinetics of CsA-NCs in cells were studied. Uptake mechanisms were also evaluated using endocytotic inhibitors and low temperature (4 °C). The cell monolayers were incubated with each diameter CsA-NCs to evaluate the effect of size on the permeation characteristics of CsA across the intestinal mucosa. The results of dissolution study showed that 165 nm CsA-NC had the highest dissolution rate followed by 240 CsA-NC and finally 450 nm CsA-NC. The saturation of cell uptake of CsA-NCs was observed with the increase of incubation concentration and time. 240 nm and 450 nm CsA-NCs had the lowest and highest uptake efficiency at different time and drug concentration, respectively. The uptake of all three-sized CsA-NCs declined significantly in some different degree after the pre-treatment with different endocytosis inhibitors. 165 nm CsA-NC showed a highest transport capacity across monolayers at the same concentration and time. The results suggest that the size of CsA-NCs can not only affect the efficiency of cellular uptake, but also the type of endocytosis. Decreasing particle size of CsA-NCs can improve transport capacity of CsA through cell monolayer.

Enhanced aqueous dissolution of hydrophobic apixaban via direct incorporation of hydrophilic nanographene oxide

In this study, we have directly incorporated nanographene oxide (nGO) into a hydrophobic drug for enhanced dissolution performance through an antisolvent technique. Apixaban (APX) drug composites were synthesized with nGO incorporation ranging from 0.8% to 2.0% concentration. It was observed that the nGO was successfully embedded without any changes to the original drug crystal structure or physical properties. Dissolution of the drug composites was evaluated using US Pharmacopeia Paddle Method (USP 42). The time needed to reach a 50% release (T50) reduced from 106 min to 24 min with the integration of 1.96% nGO in APX and the T80 also dropped accordingly. Alternatively, dissolution rate showed promising performance with increase in nGO concentration. Initial dissolution rate increased dramatically from 74 µg/min to 540 µg/min. Further, work done in intestinal media revealed T50 went from not dissolving to 79.0 min. Decreased lipophilicity or logP value and increased aqueous solubility are both accredited to hydrophilic nGO water dispersion, producing a hydrophilic channel into the drug crystal surfaces through intermolecular interaction. Additionally, physical, and chemical characterizations confirm that hydrophobic apixaban was successfully transformed into a hydrophilic composite, showing potential for this technology to improve dissolution rate of a model hydrophobic compound.

Formulation and Evaluation of Lamotrigine Loaded Nanosponges

The main purpose of this investigation study is to fabricate nanosponges with good entrapment efficiency and percentage of yield to enhance the solubility and dissolution rate of poorly water soluble antiepileptic molecules of Lamotrigine, which belongs to BCS - II class. Lamotrigine nanosponges were prepared using emulsion solvent diffusion technique and the immediate release tablets of lamotrigine nanosponges were prepared by direct compression method. Nanosponges were formulated using different polymers ratio like EC and PVA. The optimized batch containing ratio 2:1:2 of drug, ethyl cellulose and PVA shows maximum entrapment efficiency and percentage of yield. The optimized nanosponges of lamotrigine (F1) were subjected for Practical yield, drug content, Saturation solubility, zeta potential, Fourier transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Scanning electron microscopy(SEM). The optimized formulations (F1) of nanosponge based immediate release tablets compression parameters were also studied. The In-vitro dissolution was carried out by USP apparatus type II (Paddle Method) with 900 ml of 0.1 N HCl at 50 rpm. At definite time intervals, 5 ml of the receptor fluid were withdrawn, filtered and analyzed spectro-photometrically at wave length 265 nm. The compressed lamotrigine nanosponge shows 99.7% at the end of dissolution and it follows first order kinetics and best fit with Higuchi’s model. In this research solubility and dissolution demonstrated for nanosponge formulation.

In vitro Comparative Dissolution Studies of Different Propranolol Generic Tablets Available in Bangladesh

The present study focused to assess in vitro dissolution profiles of four different products of propranolol 10 mg Tablets (Randomly coded as PRP1-PRP4) available in Bangladesh comparing with the reference brand (coded as REF). Propranolol is a competitive non selective beta-adrenergic receptor antagonist used to amend or restore normal heart rhythm in cardiovascular diseases. An in vitro dissolution study was carried out using the United States Pharmacopoeia (USP) paddle method at 75 rpm with 500 mL of 0.1N HCl dissolution media at 37.0± 0.5 0C. All the tested locally manufactured propranolol products; PRP1, PRP2, PRP3, PRP4 showed compatible dissolution (87%, 86%, 87%, and 80%, respectively) pattern (dissolution criterion Q=80% in 30 minutes) compared with the reference brand (88% dissolution in 30 minutes). The dissolution behavior was estimated with the reference brand using a model dependent and model-independent approach (f2>50, f1 < 15). A mechanistic mathematical release kinetics was also evaluated. The best-fit kinetic model was Hixon-Crowell release kinetics for reference brand and PRP1; and first order release kinetics was predominant for PRP2, PRP3 and PRP4.
 Keywords: propranolol, dissolution, similarity factor, difference factor, dissolution kinetics

Characterization of Celecoxib β-Cyclodextrin Inclusion Complexes Using Solvent Evaporation Method

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of pain and inflammation. Celecoxib is included in class II in the Biopharmaceutis ClassificationAsystem drug (BCS) which has low solubility and high permeability. This study aims to increase the solubility and dissolution rate of celecoxib by characterizing the inclusion complex of celecoxib β-cyclodextrin. Inclusion complexes were prepared by the solvent evaporation method using a water-soluble polymer, β-cyclodextrin. The inclusion complexes were prepared in a 1: 1 ratio between celecoxib and β-cyclodextrins. As a comparison, a physical mixture with the same composition was made. Powder mixtures of physics and inclusion complexes characterized by physicochemical properties include: FT-IR spectroscopy analysis, DSC analysis, assay and dissolution test. The dissolution test was determined by the paddle method. The results of characterization of the inclusion complex using FT-IR spectrophotometry showed a shift in the wave number as well as the physical interaction between celecoxib and β-cyclodextrin. The results of the DSC (Differential Scanning Calorimetry) decreased the enthalpy and melting point between celecoxib, the physical mixture and the inclusion complex. The dissolution test showed an increase in dissolution rate at 60 minutes, namely Celecoxib 55.03%, physical mixture 61.58% and inclusion complex 67.53%.

IMPROVEMENT OF THE DISSOLUTION PROFILE OF SIMVASTATIN TABLETS WITH THE ADDITION OF CREMOPHOR-EL USING WET GRANULATION METHOD

Objective: Simvastatin is a drug used as a first-line anti-cholesterol in the treatment of dyslipidemia. Low solubility will affect its ability to penetrate the digestive tract membrane and will affect the amount of drug levels in the plasma. The use of Cremophor-EL as a surfactant has been shown to inhibit the action of P-glycoprotein so that it can increase the bioavailability of a drug and can increase the effect of a drug.
 Methods: The preparation of simvastatin tablets was carried out using the wet granulation method. The dissolution test used the paddle method, a speed of 50 rpm at a temperature of 37±0.5 ° C with a phosphate buffer pH 7.0 as the dissolution medium.
 Results: The results showed that at 30 min the generic simvastatin tablets had 81.52% dissolution and the Simvastatin Tablets with Cremophor-EL were 85.520%.
 Conclusion: Simvastatin cremophor-EL tablets are more dissolved than generic simvastatin at 30 min so that cremophor-EL simvastatin tablets have a better dissolution rate than generic simvastatin tablets.

Formulation and Evaluation of colon targeted drug Delivery of Diloxanide furoate Tablets using pH Dependent Polymers

Diloxanide Furoate is a Dichloroacetamide derivative utilized for the treatment of various protozoal infections like amoebiasis. Colon targeted tablets were designed using pH sensitive polymers like Eudragit S100, Eudragit L 100,Cellulose acetate phthallate at different concentrations. All the matrix,compression coated formulations showed the desired physicochemical properties as per the official limits. The drug release studies were performed according to the USP paddle method by using 0.1N HCL for 2 hours, pH 7.4 phosphate buffer for 3 hours and pH 6.8 phosphate buffer upto 18 hours. A better controlled drug release was shown for Eudragit L 100. Based on the comparative drug release studies among different Formulations F9 with Eudragit L 100 polymer showed better control drug release. The release kinetics for the Optimised Formulation F9 was calculated and “r2” value was more for Zero order kinetics i.e.,0.970 indicating that the formulation doesnot depend upon its concentration and from the Korsmeyer peppas model the diffusion exponent value “n” is > 1 indicating that it follows super case II transport mechanism. The accelerated stability studies conducted for optimised formulation F9 for 3 months have no significant variation.

Enteric complex layer-coated controlled release of capsaicin from phytosterol/γ-cyclodextrin microparticles via guest exchange reaction with taurocholic acid

Phytosterol (PSE)/γ-cyclodextrin (γ-CD) microparticles have a capsule-like structure, wherein the hydrophobic PSE core is surrounded by outer layers of the hydrophilic PSE/γ-CD inclusion complex crystal. The microparticles could mask the undesirable taste of capsaicin (CAP) by encapsulation of CAP into the microparticles. In the present study, the dissolution of CAP from PSE/γ-CD microparticles into artificial intestinal fluids was examined using the paddle method. The dissolution of CAP from the microparticles was suppressed at pH 1.2 and 5.0. On the other hand, the dissolution was significantly enhanced in fasted and fed state simulated intestinal fluid (FaSSIF and FeSSIF) . Taurocholate (TCA), contained in these artificial fluids, induced rapid dissolution of CAP from microparticles. The mechanism of CAP dissolution from the microparticles in the presence of TCA was investigated using in situ1H NMR spectroscopy. During the incubation of the mixed suspension of the microparticles and TCA, γ-CD peaks started to appear, and the TCA peak showed a gradual upfield shift. Quantitative analysis of NMR results showed that the TCA/γ-CD inclusion complex could form during incubation, according to the dissolution of γ-CD from the microparticles via the guest exchange reaction of PSE by TCA. The collapse of the PSE/γ-CD inclusion complex crystal at the outer shell of microparticles could trigger the release of CAP into the intestinal fluid. Thus, PSE/γ-CD microparticles can be used as an enteric controlled-release system that releases encapsulated drugs not via the conventional pH changes but via guest exchange reaction with TCA.

FORMULATION DEVELOPMENT AND EVALUATION OF ONCE DAILY SUSTAINED RELEASE METFORMIN HYDROCHLORIDE TABLETS

Metformin hydrochloride has relatively short plasma half-life and low absolute bioavailability. The need of administration for two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 20 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic alone or its combination with hydrophobic as rate controlling factor. The tablets were prepared by granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method. The drug release study revealed that HPMC alone was unable to sustain the drug release. Combining HPMC 8 HEC and coting with a semi-permeable membrane with controlled release from an orifice, sustained the drug release for more than 20h.

Optimization of Nanostructured Lipid Carriers of Fenofibrate Using a Box-Behnken Design for Oral Bioavailability Enhancement.

Fenofibrate (FNB) is a commonly used hypolipidemic agent. However, the oral bioavailability of FNB is limited by slow dissolution due to its low solubility. Thus, investigations on novel FNB formulations are necessary for their use. The objective of this study is to enhance the oral bioavailability of FNB using optimized Nanostructured Lipid Carrier (NLC) formulations. Hot homogenization followed by ultrasonication was used to prepare FNB-NLCs. These formulations were optimized using a Box-Behnken design, where the amount of FNB (X1), a ratio of solid lipid/liquid lipid (X2), and the percentage of emulsifier (X3) were set as independent variables, while the particle size (Y1), and Entrapment Efficiency (EE%) (Y2), were used as dependent factors. An in vitro dissolution test was then performed using a paddle method, while an in vivo pharmacokinetic study of FNB-NLC formulation was performed in rats. FNB-NLCs were successfully prepared and optimized using a Box-Behnken design. The particle size and EE% of the FNB-NLC had less than 5% difference from predicted values. The in vitro dissolution and oral bioavailability of the FNB-NLC were both higher than those of raw FNB. A Box-Behnken design was successfully applied to optimize FNB-NLC formulation for the enhancement of the dissolution and bioavailability of FNB, a poorly water-soluble drug.

Hydrophilic and Functionalized Nanographene Oxide Incorporated Faster Dissolving Megestrol Acetate.

The aim of this work is to present an approach to enhance the dissolution of progestin medication, megestrol acetate (also known as MEGACE), for improving the dissolution rate and kinetic solubility by incorporating nano graphene oxide (nGO). An antisolvent precipitation process was investigated for nGO-drug composite preparation, where prepared composites showed crystalline properties that were similar to the pure drug but enhanced aqueous dispersibility and colloidal stability. To validate the efficient release profile of composite, in vitro dissolution testing was carried out using United States Pharmacopeia, USP-42 paddle method, with gastric pH (1.4) and intestinal pH (6.5) solutions to mimic in vivo conditions. Pure MA is practically insoluble (2 µg/mL at 37 °C). With the incorporation of nGO, it was possible to dissolve nearly 100% in the assay. With the incorporation of 1.0% of nGO, the time required to dissolve 50% and 80% of drug, namely T50 and T80, decreased from 138.0 min to 27.0 min, and the drug did not dissolve for 97.0 min in gastric media, respectively. Additionally, studies done in intestinal media have revealed T50 did not dissolve for 92.0 min. This work shows promise in incorporating functionalized nanoparticles into the crystal lattice of poorly soluble drugs to improve dissolution rate.

Formulation and evaluation of mucoadhesive buccal tablets of aceclofenac

This project was aimed to formulate and characterize mucoadhesive buccal tablets of aceclofenac, utilizing different proportions of three polymers carbopol 934, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose. Twelve batches of buccoadhesive aceclofenac were prepared by the direct compression method. The compressed tablets were then evaluated for physicochemical parameters such as hardness, thickness, weight variation, drug content, friability, swelling index, surface pH, and ex vivo mucoadhesion. In vitro dissolution test was conducted for 12 h according to Indian Pharmacopeia 2018, using the rotating paddle method in phosphate buffer of pH 7.4. Physiochemical parameters like weight variation (231.25–268.75 mg), hardness (8.32–11.56 kg), friability (0.04–0.2%), diameter (9.00 mm), thickness (3.8–4.05 mm), and drug content ((97.67–102.25%) were within the acceptable limit as per Indian Pharmacopeia 2018. The swelling index was reported to be in the range of 112.93–450.19%, at 8 h. The surface pHs of all the batches were in between 6.72 to 6.96. The mucoadhesive strengths (40.5–50 g) varied with the change in polymer concentrations especially of carbopol 934. The dissolution profile of all the batches varied greatly, with a maximum release of 109.41% (in batch 12 at 6 h) to a minimum release of 44.82% (in batch 3 at 12 h). Among them, only batch 1 ensured sustained and effective drug release (88.34% at 12 h) with appropriate swelling index (112.93%) and mucoadhesive strength (40 g). Fourier Transform Infrared Spectroscopy analysis showed no evidence of drug excipients interaction. Hence, the results concluded that buccal mucoadhesive aceclofenac tablets can be formulated. Furthermore, the property of the tablet not only depends on the concentration but also the behavior of the polymers used.

Effect of Different Carriers on In Vitro and In Vivo Drug Release Behavior of Aceclofenac Proniosomes.

Improved bioavailability of Aceclofenac (ACE) may be achieved through proniosomes, which are considered as one of the most effective drug delivery systems and are expected to represent a valuable approach for the development of better oral dosage form as compared to the existing product. However, the carrier in this system plays a vital role in controlling the drug release and modulating drug dissolution. Accordingly, a comparative study on different carriers can give a clear idea about the selection of carriers to prepare ACE proniosomes. This study aims to evaluate the role of maltodextrin, glucose, and mannitol as carriers for in vitro and in vivo performance of Aceclofenac (ACE) proniosomes. Three formulations of proniosomes were prepared by the slurry method using the 100 mg ACE, 500 mg span 60, 250 mg cholesterol with 1300mg of different carriers, i.e., glucose (FN1), maltodextrin (FN2), and mannitol (FN3). In vitro drug release studies were conducted by the USP paddle method, while in vivo studies were performed in albino rats. Pure ACE was used as a reference in all the tests. Lastly, the results were analyzed using the High-Pressure Liquid Chromatography (HPLC) method, and data were evaluated using further kinetic and statistical tools. No significant differences (p > 0.05) in entrapment efficiency (%EE) of FN1, FN2, and FN3 (82 ± 0.5%, 84 ± 0.66%, and 84 ± 0.34% respectively) were observed and formulations were used for further in vitro and in vivo evaluations. During in vitro drug release studies, the dissolved drug was found to be 42% for the pure drug, while 70%, 17%, and 30% for FN1, FN2, and FN3, respectively, at 15 min. After 24 hrs, the pure drug showed a maximum of 50% release while 94%, 80%, and 79% drug release were observed after 24 hr for FN1, FN2, and FN3, respectively. The in vivo study conducted on albino rats showed a higher Cmax and AUC of FN1 and FN2 in comparison with the pure ACE. Moreover, the relative oral bioavailability of proniosomes with maltodextrin and glucose as carriers compared to the pure drug was 183% and 112%, respectively. Mannitol- based formulation exhibited low bioavailability (53.7%) that may be attributed to its osmotic behavior. These findings confirm that a carrier plays a significant role in determining in vitro and in vivo performance of proniosomes and careful selection of carrier is an important aspect of proniosomes optimization.

PREPARATION OF SPRAY DRIED COAMORPHOUS SOLIDS TO IMPROVE THE SOLUBILITY AND DISSOLUTION RATE OF ATORVASTATIN CALCIUM

Atorvastatin calcium (AC) is a statin drug used to lower cholesterol. Its crystalline form is usually found in the market with low solubility properties. The amorphization of crystalline AC is a technique used to increase its solubility however; the amorphous form has less thermodynamic stability. Therefore, to increase the solubility properties of its crystalline form, an AC coamorphous solid was prepared. This coamorphous solid was prepared using spray drying techniques, and coformers such as isonicotinamide (INA) and maleic acid (MA). Furthermore, characterization was carried out using powder X-ray diffraction, differential scanning calorimetry, fourier transform infrared spectroscopy, and scanning electron microscopy, while the solubility properties test was conducted using the shake-flask and paddle method. The results showed that the spray-dried solids were coamorphous with single-phase homogeneous systems. Furthermore, the coamorphous solids, AC-INA and AC-MA were found to have a higher Tg than the melting points of other components, and formed intermolecular interactions between them. The higher Tg and presence of intermolecular interactions indicate that coamorphous solids are more stable than the amorphous form. Therefore, the results of the solubility and dissolution test showed that the coamorphous solid of AC-INA and AC-MA have better solubility properties compared to the AC crystalline form.

Potential Application of USP Paddle and Basket Dissolution Methods in Discriminating for Portioned Moist Snuff and Snus Smokeless Tobacco Products.

The focus of the study was to develop discriminatory dissolution methods for portioned snus and moist snuff sub-categories of smokeless tobacco products (STPs) using USP basket and paddle apparatuses. Skoal Classic Wintergreen (SCW) and CORESTA CRP1.1 pouches were used as test products. The dissolution was performed at 10, 20, 30, 40, and 50rpm basket or paddle speed in 500ml artificial saliva pH6.8. The products were also characterized for assay, pH, particle size, and loss on drying. The dissolution profiles were evaluated for amount/% of nicotine dissolved, time to reach plateau, and profiles comparison by f2 and f1 factors. The nicotine assay was 13.3 ± 0.2 and 7.6 ± 0.1mg/pouch for SCW and CRP1.1, respectively. The nicotine dissolved in 30min from SCW and CRP1.1 were 38.4-81.8 and 37.6-88.1, and 50.5-64.9 and 72.3-92.1% by paddle and basket methods, respectively. The f2 and f1 values were ≤ 39.2 and ≥42.1 and ≤ 43.2 and ≥34.1 for basket methods and paddle methods. RSD were less than 20% at all points of dissolution profiles, and dissolution plateau were achieved in 30min at some of the tested conditions. In summary, dissolution methods based on basket and paddle can be used as a performance test for STPs.

Effect of xanthan gum-based food thickeners on the dissolution profile of fluoroquinolones oral formulations

BackgroundXanthan gum-based food thickeners (XG-FTs) are often ingested by patients with dysphagia to prevent aspiration during drug treatment. Reportedly, XG-FTs affect tablet disintegration, drug dissolution rates, and reduce the efficacy of postprandial antihyperglycemic agents. The absorption rate and quantity of fluoroquinolone antimicrobial agents correlate with drug efficacy, raising concern about the impact of XG-FTs. Previously, we reported that film-coated tablets were less susceptible to the effects of XG-FT than conventional and orally disintegrating tablets. Here, we compare the effect of XG-FTs on dissolution profiles of three oral fluoroquinolone-based film-coated tablets by evaluating the dissolution of crushed products, fine granules, and film-coated fine granules.MethodsWe examined formulations of tosufloxacin tosylate monohydrate (TFLX), levofloxacin hemihydrate (LVFX), and ciprofloxacin hydrochloride hydrate (CPFX). The formulations were immersed in 20 mL of 1.5% (w/v) XG-FT aqueous solution for 2.5 min followed by a dissolution test using the paddle method according to the Japanese Pharmacopoeia (dissolution test solution pH 1.2; volume 900 mL; temperature 37 ± 0.5 °C). The dissolution profile was evaluated according to the dissolution quantity indicated in product specifications and guidelines for bioequivalence testing of generic drugs. The 15-min mean dissolution rate was determined for a formulation immersed in 1.5% (w/v) XG-FT aqueous solution and compared with that for a non-immersed formulation (control). Fluoroquinolone film-coated tablets were mixed with starch-based FTs, guar gum-based FTs, or XG-FTs to observe their appearances.ResultsThe dissolution profile of LVFX film-coated tablets was not affected by XG-FTs, but the dissolution of TFLX and CPFX was delayed. For crushed film-coated tablets, the 15-min mean dissolution rate was significantly delayed for all three fluoroquinolones when compared with that of uncrushed products. The dissolution profile of TFLX film-coated fine granules was unchanged by XG-FTs. CPFX film-coated tablets and crushed products produced a gel-like precipitate when mixed with XG-FTs and failed to meet product-dissolution specifications. A gel-like precipitate was also observed with guar gum-based FTs.ConclusionThe effect of XG-FTs on the dissolution profile of film-coated fluoroquinolone formulations varied depending on the formulation. The CPFX formulation formed a gel-like precipitate when immersed in XG-FTs resulting in a significantly delayed dissolution.

Effect of mesoporous characteristics on competitive adsorption kinetics of uremic-like toxin and atorvastatin on spherical carbon adsorbents for an in vitro chronic renal failure therapeutic model

Indole-3-acetic acid (IA, urine-like toxin) coexisting with atorvastatin (AT) was adsorbed by spherical carbonaceous adsorbents (SCs). The relationship between the competitive adsorption kinetics and the mesoporous structures was investigated. The pore structures of the four SCs were analyzed using the Hg and gas adsorption methods. SC adsorption tests were performed using the dissolution test with the paddle method with an SC sample in distilled water containing IA and/or AT at 37.0 °C. The amounts of IA and AT adsorbed on SCs in single- and binary-drug administration tests were measured based on the ultraviolet-visible spectra using classical least squares analysis. Rate constants for the drug adsorption of IA and AT by SCs (kIA and kAT, respectively) were suppressed by the effect of coexisting drugs. The suppression of IA adsorption by the coexisting drug was dependent on the pore structure of the SCs. kIA and kAT against the SCs were competitively inhibited by coexisting drugs.