Engineering Active Pharmaceutical Ingredients by Spray Drying: Effects on Physical Properties and In Vitro Dissolution

Active pharmaceutical ingredients have very strict quality requirements; minor changes in the physical and chemical properties of pharmaceuticals can adversely affect the dissolution rate and therefore the bioavailability of a given drug. Accordingly, the aim of the present study was to investigate the effect of spray drying on the physical and in vitro dissolution properties of four different active pharmaceutical ingredients, namely carbamazepine, indomethacin, piroxicam, and nifedipine. Each drug was dispersed in a solution of ethanol and water (70:30) and subjected to single-step spray drying using similar operational conditions. A complete characterization of the spray-dried drugs was performed via differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), particle size distribution analysis, solubility analysis, and an in vitro dissolution study. The results from the thermal analysis and X-ray diffraction showed that, except for carbamazepine, no chemical modifications occurred as a result of spray drying. Moreover, the particle size distribution of all the spray-dried drugs significantly decreased. In addition, SEM images showed that most of the particles had an irregular shape. There was no significant improvement in the solubility of the spray-dried drugs compared with the unprocessed compounds; however, in general, the dissolution rates of the spray-dried drugs showed a remarkable improvement over their non-spray-dried counterparts. Therefore, the results from this study demonstrate that a single spray-drying step may lead to changes in the physical properties and dissolution characteristics of drugs and thus improve their therapeutic action.

A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. II. Dissolution studies and in vitro/in vivo correlation

The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel® worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro-in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r=0.773; p<.00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro-in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration-time profiles.

Estabilidade, polimorfismo, dissolução e correlação in vivo-in vitro de Darunavir comprimidos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

In Vitro Release from Reverse Poloxamine/alpha-Cyclodextrin Matrices: Modelling and Comparison of Dissolution Profiles

Gels obtained by complexation of octablock star polyethylene oxide/polypropylene oxide copolymers (Tetronic 90R4) with -cyclodextrin (-CD) were evaluated as matrices for drug release. Both molecules are biocompatible so they can be potentially applied to drug delivery systems. Two different types of matrices of Tetronic 90R4 and -CD were evaluated: gels and tablets. These gels are capable to gelifying in situ and show sustained erosion kinetics in aqueous media. Tablets were prepared by freeze-drying and comprising the gels. Using these two different matrices, the release of two model molecules, L-tryptophan (Trp), and a protein, bovine serum albumin (BSA), was evaluated. The release profiles of these molecules from gels and tablets prove that they are suitable for sustained delivery. Mathematical models were applied to the release curves from tablets to elucidate the drug delivery mechanism. Good correlations were found for the fittings of the release curves to different equations. The results point that the release of Trp from different tablets is always governed by Fickian diffusion, whereas the release of BSA is governed by a combination of diffusion and tablet erosion. 

Effect of Iron II on Hydroxyapatite Dissolution and Precipitation in vitro

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

In vitro evaluation of Biosilicate® dissolution on dentin surface: a SEM analysis

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Poloxamer-based binary hydrogels for delivering tramadol hydrochloride: sol-gel transition studies, dissolution-release kinetics, in vitro toxicity, and pharmacological evaluation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of trimetaphosphate and fluoride association on hydroxyapatite dissolution and precipitation in vitro

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The influence of saliva on the dissolution of calcium fluoride after application of different fluoride gels in vitro

OBJECTIVE: To determine the formation and dissolution of calcium fluoride on the enamel surface after application of two fluoride gel-saliva mixtures. METHOD AND MATERIALS: From each of 80 bovine incisors, two enamel specimens were prepared and subjected to two different treatment procedures. In group 1, 80 specimens were treated with a mixture of an amine fluoride gel (1.25% F-; pH 5.2; 5 minutes) and human saliva. In group 2, 80 enamel blocks were subjected to a mixture of sodium fluoride gel (1.25% F; pH 5.5; 5 minutes) and human saliva. Subsequent to fluoride treatment, 40 specimens from each group were stored in human saliva and sterile water, respectively. Ten specimens were removed after each of 1 hour, 24 hours, 2 days, and 5 days and analyzed according to potassium hydroxide-soluble fluoride. RESULTS: Application of amine fluoride gel resulted in a higher amount of potassium hydroxide-soluble fluoride than did sodium fluoride gel 1 hour after application. Saliva exerted an inhibitory effect according to the dissolution rate of calcium fluoride. However, after 5 days, more than 90% of the precipitated calcium fluoride was dissolved in the amine fluoride group, and almost all potassium hydroxide-soluble fluoride was lost in the sodium fluoride group. Calcium fluoride apparently dissolves rapidly, even at almost neutral pH. CONCLUSION: Considering the limitations of an in vitro study, it is concluded that highly concentrated fluoride gels should be applied at an adequate frequency to reestablish a calcium fluoride-like layer.

Determination of absorption curves, dissolution profiles and establishment of in vitro-in vivo correlation by in silico methods using GastroPlusTM and DDDPlusTM

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work.

Dissolution rate enhancement, in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions. © 2013 Informa Healthcare USA, Inc.

Physicochemical characterisation, drug polymer dissolution and in vitro evaluation of phenacetin and phenylbutazone solid dispersions with polyethylene glycol 8000

Poor water solubility leads to low dissolution rate and consequently, it can limit bioavailability. Solid dispersions, where the drug is dispersed into an inert, hydrophilic polymer matrix can enhance drug dissolution. Solid dispersions were prepared using phenacetin and phenylbutazone as model drugs with polyethylene glycol (PEG) 8000 (carrier), by melt fusion method. Phenacetin and phenylbutazone displayed an increase in the dissolution rate when formulated as solid dispersions as compared with their physical mixture and drug alone counterparts. Characterisation of the solid dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). DSC studies revealed that drugs were present in the amorphous form within the solid dispersions. FTIR spectra for the solid dispersions of drugs suggested that there was a lack of interaction between PEG 8000 and the drug. However, the physical mixture of phenacetin with PEG 8000 indicated the formation of hydrogen bond between phenacetin and the carrier. Permeability of phenacetin and phenylbutazone was higher for solid dispersions as compared with that of drug alone across Caco-2 cell monolayers. Permeability studies have shown that both phenacetin and phenylbutazone, and their solid dispersions can be categorised as well-absorbed compounds.

PEG-based solid dispersions enhanced the solubility and dissolution of eprosartan mesylate in-vitro

Abstract - This study investigates the effect of solid dispersions prepared from of polyethylene glycol (PEG) 3350 and 6000 Da alone or combined with the non-ionic surfactant Tween 80 on the solubility and dissolution rate of a poorly soluble drug eprosartan mesylate (ESM) in attempt to improve its bioavailability following its oral administration.

INTRODUCTION

ESM is a potent anti-hypertension [1]. It has low water solubility and is classified as a Class II drug as per the Biopharmaceutical Classification Systems (BCS) leading to low and variable oral bioavailability (approximately 13%). [2]. Thus, improving ESM solubility and/or dissolution rate would eventually improve the drug bioavailability. Solid dispersion is widely used technique to improve the water solubility of poorly water-soluble drugs employing various biocompatible polymers. In this study, we aimed to enhance the solubility and dissolution of EMS employing solid dispersion (SD) formulated from two grades of poly ethylene glycol (PEG) polymers (i.e. PEG 3350 & PEG 6000 Da) either individually or in combination with Tween 80.

MATERIALS AND METHODS

ESM SDs were prepared by solvent evaporation method using either PEG 3350 or PEG 6000 at various (drug: polymer, w/w) ratios 1:1, 1:2, 1:3, 1:4, 1:5 alone or combined with Tween 80 added at fixed percentage of 0.1 of drug by weight?. Physical mixtures (PMs) of drug and carriers were also prepared at same ratios. Drug solid dispersions and physical mixtures were characterized in terms of drug content, drug dissolution using dissolution apparatus USP II and assayed using HPLC method. Drug dissolution enhancement ratio (ER %) from SD in comparison to the plain drug was calculated. Drug-polymer interactions were evaluated using Differential Scanning Calorimetry (DSC) and FT-IR.

RESULTS AND DISCUSSION

The in vitro solubility and dissolution studies showed SDs prepared using both polymers produced a remarkable improvement (p<0.05) in comparison to the plain drug which reached around 32% (Fig. 1). The dissolution enhancement ratio was polymer type and concentration-dependent. Adding Tween 80 to the SD did not show further dissolution enhancement but reduced the required amount of the polymer to get the same dissolution enhancement. The DSC and FT-IR studies indicated that using SD resulted in transformation of drug from crystalline to amorphous form.

CONCLUSIONS

This study indicated that SDs prepared by using both polymers i.e. PEG 3350 and PEG 6000 improved the in-vitro solubility and dissolution of ESM remarkably which may result in improving the drug bioavailability in vivo.

Acknowledgments

This work is a part of MSc thesis of O.M. Ali at the Faculty of Pharmacy, Aleppo University, Syria.

REFERENCES

[1] Ruilope L, Jager B: Eprosartan for the treatment of hypertension. Expert Opin Pharmacother 2003; 4(1):107-14

[2] Tenero D, Martin D, Wilson B, Jushchyshyn J, Boike S, Lundberg, D, et al. Pharmacokinetics of intravenously and orally administered Eprosartan in healthy males: absolute bioavailability and effect of food. Biopharm Drug Dispos 1998; 19(6): 351- 6.