|Year : 2021 | Volume
| Issue : 1 | Page : 77-86
Improvement of bioavailability of poorly soluble racecadotril by solid dispersion with surface adsorption method: A case study
Bhaskar Daravath1, Girmannagari Prasanna Kumari2
1 Department of Pharmaceutics, School of Pharmacy, GITAM Deemed to be University, Hyderabad, Telangana, India
2 Sri Shivani College of Pharmacy, Hanamkonda, Warangal, Telangana, India
|Date of Submission||06-Dec-2019|
|Date of Acceptance||30-Aug-2020|
|Date of Web Publication||31-May-2021|
Dr. Bhaskar Daravath
School of Pharmacy, GITAM Deemed to be University, Rudraram (V), Patancheru (M), Sanga Reddy (D), Telangana.
Source of Support: None, Conflict of Interest: None
Introduction: Biopharmaceutics classification system class II drugs show unpredictable bioavailability based on their solubility. Unfortunately, very few products were manufactured by this technique owing to their poor flowability and stability. The objective of the current investigation was used to improve the flowability by surface solid dispersion (SSD; SD with surface adsorption technology) and improve the absorption of racecadotril (RT) under low pH conditions (i.e., in stomach) to show anti-diarrheal effect by reducing water and electrolyte secretion into the intestine. Materials and Methods: SSDs and physical mixtures (PMs) were prepared using various ratios of hydrophilic carriers (polyethylene glycol 4000, polyethylene glycol 6000, and Gelucire 50/13) and an adsorbent (lactose monohydrate). Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry , and dissolution studies (in vitro) were conducted to characterize SSDs and PMs. Results: Phase solubility curves represent AL type, indicating that the solubility of drug linearly increased with an increase in the concentration of carrier. Characterization studies indicated that no interactions between carrier and drug. Solid-state characterization showed a reduction in crystallinity that further supports increment in solubility and dissolution. The optimized formulation (SDG4) showed 99.84 ± 1.5% drug release in 15 min compared to RT plain drug (11.95 ± 1.72%). In vivo bioavailability studies of SDG4 revealed a significant (P < 0.05) increase in Cmax 65.38 ± 1.34 µg/mL (1.75-fold) with increased relative bioavailability (180.22-fold) against the RT plain drug. Conclusion: Formulation of SD with surface adsorption method could enhance solubility, dissolution, and bioavailability of RT.
Keywords: Bioavailability, flowability, gelucire, solubility, surface solid dispersion
|How to cite this article:|
Daravath B, Kumari GP. Improvement of bioavailability of poorly soluble racecadotril by solid dispersion with surface adsorption method: A case study. J Rep Pharma Sci 2021;10:77-86
|How to cite this URL:|
Daravath B, Kumari GP. Improvement of bioavailability of poorly soluble racecadotril by solid dispersion with surface adsorption method: A case study. J Rep Pharma Sci [serial online] 2021 [cited 2021 Jun 15];10:77-86. Available from: https://www.jrpsjournal.com/text.asp?2021/10/1/77/317258
| Introduction|| |
Poorly water-soluble drugs exhibit bioavailability problems, especially when they are orally administered. Dissolution is the rate-determining step for absorption of a drug to show therapeutic activity. Poorly water-soluble drugs show unpredictable absorption as compared to highly soluble drugs.
Solid dispersion (SD) uses homogeneous dispersion of poor soluble drugs in a hydrophilic carrier to improve solubility and dissolution and thereby bioavailability. The mechanism for enhancement of the dissolution of SD is solid-state transformation from crystalline to amorphous form, molecule-level reduction in particle size, improvement of wettability, and solubility of a drug by hydrophilic carriers in the surrounding environment.,, However, the obtained SD was so tacky and sticky and leads to a decrease in yield recovery. This problem will reflect in handling and subsequently in the processes of manufacturing. It also affects the flow property and stability of the product.
Nowadays new approaches are used to get control of these problems and also improve the bioavailability of drug using SD with surface adsorption technique by adsorbing on the inert core of adsorbent.,, This technology has been successfully used for a variety of drugs such as ibuprofen, piroxicam, meloxicam, itraconazole, aceclofenac, and smvastatin.
In all age group of people, the commonly affecting illness is diarrhea. It is associated with excessive loss of water and electrolyte. Racecadotril (RT) is an enkephalinase inhibitor used to treat acute diarrhea. It has an antisecretory effect by reducing intestinal motility and thereby reduces electrolyte and water secretion into the intestine. It also decreases the abdominal pain and reduces the duration and frequency of acute diarrhea.,
RT comes under BCS (Biopharmaceutics classification system) class II drug with low bioavailability. The time of peak plasma concentration of conventional RT tablets is ~1 h. But it needs a faster onset of action to prevent the excessive loss of fluid. Hence, an attempt has been made to develop a new RT dosage form to overcome this limitation.
In this present study, RT SD was prepared using carriers such as polyethylene glycol 4000, polyethylene glycol 6000, and Gelucire 50/13. Surface adsorbents further promote the flow property of SD, stability, and absorption of RT that improves bioavailability and drug’s acceptability.
| Materials and Methods|| |
RT was obtained ex gratis by M/S Symed Laboratory Limited, (Hyderabad, India). PEG 4000 and 6000 were provided by Qualikems Fine Chemicals Private Limited (Vadodara, India), and Gelucire 50/13 was provided ex gratis by M/S Gattefosse Private Limited (Mumbai, India). Chemicals, reagents, and excipients were used of analytical grade.
RT phase solubility studies
The shake flask method was employed for carrying phase solubility studies to measure the solubility of RT. An amount of RT, more than saturation, was placed in a test tube having different concentrations of polyethylene glycol 4000, polyethylene glycol 6000, and Gelucire 50/13 (0, 5, 10, 15, 20, 25, and 30% w/v) solution separately. The tubes were sonicated for 15 min and stirred continuously on a shaker at room temperature for 48 h. After centrifugation, the supernatant of the suspensions was passed through a membrane filter (0.45 µm) and the content of RT was measured using ultraviolet-visible spectroscopy at 231 nm. Gelucire 50/13 does not show the absorbance at 231 nm.
Apparent stability constant at 1:1 (Ks) was determined using the phase solubility curve
where So is solubility of RT in water.
Aqueous solubility of RT was expressed by Gibbs transfer of free energy
and it was calculated by the following equation:
where Ss/So is the solubility ratio of RT in polymeric solution to water.
Preparation of SD with surface adsorption and physical mixtures
Preparation of SD with surface adsorption
SDs of RT were formulated in different ratios [Table 1] using a different drug to carrier ratio by melt method. The carriers selected for the formulation of SD were polyethylene glycol 4000, polyethylene glycol 6000, and Gelucire 50/13 at a different drug to carrier ratio as given in [Table 1]. The carrier was taken on a Petri plate and melted by placing on a water bath. Then, the drug was incorporated by continuously stirring into a molten polymer. Then, the mixture was cooled to 25°C. Lactose monohydrate (adsorbent) was added to the molten mass during the cooling process and mixed continuously. The prepared SSDs were collected and sieved through 60 # and stored in desiccators.
|Table 1: Formulation of RT surface solid dispersions using various carriers|
Click here to view
Formulation of RT physical mixture
All physical mixtures (PMs) of RT were prepared by initially crushing all the carriers to fines using a mortar individually for 10 min [Table 1] in four ratios. PMs were prepared by triturating drug, carrier, and adsorbent in a mortar with pestle and passed through 60 # sieve to get a homogeneous mixture.
Evaluation of SD with surface adsorbent
Determination of drug content
SD with surface adsorbents (SSDs) was accurately weighed and dissolved in methanol. The samples were mixed in a bath sonicator for 10 min. The resulting samples were filtered through a membrane filter (0.45 µ). The clear solution was appropriately diluted with 0.1N HCl and RT drug content was determined from the calibration curve. The calibration curve was prepared by dissolving the pure RT in 0.1N HCl. The sample solutions (2 to 10 µg/mL) were prepared using 0.1N HCl and analyzed by ultraviolet-visible spectroscopy at 231 nm.
Flow properties of SD with surface adsorbent
Flow properties of the powder blend were measured by determining the angle of repose and Carr’s compressibility index by the following equation:
where θ was angle of repose, and radius and height of pile were R and H, respectively. Carr’s index was measured by
where ρb is bulk density and ρp is tapped density.
In vitro dissolution and data treatment
In vitro dissolution studies of RT, SSDs, and PMs were carried out using USP paddle apparatus II (UV3000+, Lab India Solutions, Mumbai, India) containing 0.1N HCl (900 mL) at 37 ± 0.5°C for 50 rotations per minute. The amount of RT was equivalent to 100 mg in all formulations. An aliquot (5 mL) was removed at suitable time point and replaced by an equal amount of unused buffer. An aliquot was passed through membrane filters (0.45 µm) and the contents were spectrometrically analyzed at 231 nm. Mean values were reported by performing the studies in triplicate. Dissolution profiles were analyzed and compared for various parameters, cumulative percent drug release Q15 (in 15 min), MDT (mean dissolution time), and % DE (% dissolution efficiency) at 15 min.
Characterization of SD with surface adsorbent
FTIR spectrum of plain RT, Gelucire 50/13, PMG4, and SDG4 was recorded on a FTIR spectroscopy (IRTracer-100, Shimadzu, Japan) between 400 and 4000 cm−1 by potassium bromide pellet method. A differential scanning calorimeter (DSC-60A, Shimadzu, Japan) was used to record the thermograms of RT, Gelucire 50/13, PM (PMG4), and optimized SSDs (SDG4). Approximately 5–7 mg sample was heated in an aluminum pan under the flow of nitrogen gas for a range of temperature of 0 to 400°C at 5°C/min rate. X-ray diffractograms of the samples (pure RT, Gelucire 50/13, SDG4, and PMG4) were recorded using X-ray diffractometry (Siemens D5000, TX, USA) by scanning at 2θ range of 2° to 50° by exposing to Cu radiation at 30 mA current of 40kV voltage under a wavelength of 1.540 Å.
SDG4 (optimized) was stored for 6 months at 40 ± 2°C and 75 ± 5% RH (relative humidity). Drug content and % assay were determined to study the effect of conditions of storage on formulations. The similarity index (F2) was determined to find out the stability of SSD.
In vivo bioavailability studies
Bioavailability studies were planned and executed as per the approved protocol (IAEC No: VCOP/2018/13/1). In the present study, 12 albino rats weighing 190 to 210g were used. A crossover design study was used. The animals (rats) were equally divided into two groups. The first group received optimized formulation (SDG4) and the second group received pure RT at an oral dose equivalent to 10 mg per kg of body weight. Optimized formulations and pure RT were dispersed in sodium carboxymethylcellulose and the resulted suspension was administered orally. After 24 h of washout period, optimized SDG4 was administered to the second group; whereas pure RT was administered to the first group. At different time points (0, 0.125, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h), 0.5 mL of blood samples were periodically collected from retro-orbital vein in microcentrifuged tubes. After centrifugation of blood samples for 5 min at 5000 rpm, the plasma was stored at −40°C.
HPLC analysis of RT in plasma
RT concentration was quantitatively analyzed from the plasma by the high-performance liquid chromatography (HPLC) method. The analysis was carried out using RP-HPLC [Shimadzu LC-20AD, rheodyne sample injection port with 20 µL loop, SPD-M20A Photodiode array detector (PDA), Shimadzu Corporation, Japan] equipped with Kromasil C18 (250 × 4.6mm, 5 μm) column. The mobile phase consisted of 20mM phosphate buffer (pH 3.5) and acetonitrile (60:40 v/v). The eluents were monitored at a wavelength of 230 nm at a flow rate of 1 mL/min.
Ninety microliters of plasma were transferred to a microcentrifuge tube and spiked with 10 µL of internal standard (10 µg/mL gemfibrozil solution) and vortexed for 2 min. Acetonitrile (400 µL) was added to precipitate the proteins and vortexed for 5 min. The mixture was centrifuged at 5000 rpm at 5 min. The supernatant was separated and filtered through 0.45 µm membrane filter and 20 µL of the solution was injected into the HPLC system.
All the pharmacokinetic (PK) parameters were determined by PK Solver (trial version 2.0) using noncompartmental model analysis. Tmax and Cmax were obtained from the plasma concentration-time profile. The trapezoidal method was used to determine AUC and AUMC. The relative bioavailability of optimized formulation was calculated against pure RT using the following equation:
Statistical method of analysis
To investigate the differences between pure drug and optimized formulation of RT, the pharmacokinetic parameters were evaluated by paired t-test (at P = 0.05).
| Results and Discussion|| |
Phase solubility studies of RT
The results of phase solubility studies are given in [Table 2]. Aqueous solubility of RT was observed as 0.00176 mg/mL and increased linearly with an increase in carrier concentration, indicating AL-type [Figure 1]A–[C] of solubility diagram. Significant improvement in solubility was observed in the presence of Gelucire 50/13 with 115-fold improvement at 30% w/v concentration compared to pure drug. The different solubility parameters were calculated and shown in [Table 3]. Stability constant values were found to be 285.52 mL/g for PEGs and 342.97 mL/g for Gelucire 50/13, indicating that stronger interactions between carriers and drug. The negative values of Gibb’s free energy of transfer, ΔG°tr, indicate that solubilization was taking place spontaneously in aqueous polymeric solution.
|Table 2: Thermodynamic parameter (Gibb’s free energy of transfer, ) of RT in PEG 4000, PEG 6000, and Gelucire 50/13 aqueous solutions (mean ± SD, n = 3)|
Click here to view
|Figure 1: Phase solubility diagrams of RT in PEGs and Gelucire solutions at room temperature (n = 6) [(a) PEG 4000 (b) PEG 6000 (c) Gelucire 50/13]|
Click here to view
Formulation of SD with surface adsorbent (SSDs) and PM
SSDs and PMs of RT were formulated using various hydrophilic carriers and adsorbent [Table 1]. Pre-evaluation studies were conducted to select suitable adsorbent. These studies revealed that lactose monohydrate was found to be suitable compared to others adsorbents. For SDs of PEGs, 0.5g of lactose monohydrate was added. Because of sticky nature of Gelucire, about 2g of lactose monohydrate was added to get free flowing.
Evaluation of SD with surface adsorbent
Determination of drug content
Determination of RT content was performed by dissolving into a suitable media (0.1N HCl). The RT content in the SDG4 was 99.25 ± 1.26% and found to be in the range (85–115%), indicating that the content uniformity of RT was in an acceptable limit.
Flow properties of SD with surface adsorbent
Plain RT has poor flow as its angle of repose value is 42.64 ± 0.86°. Without the surface adsorbent, all the formulations are sticky and showed poor flow properties. The formulations which are prepared using adsorbent showed angles of repose are less than 30°, indicating good flow properties [Table 4]. The compressibility of surface SDs was determined by Carr’s index which was less than 18% for all formulations, indicating good flow property. The Carr’s index and angle of repose values of optimized formulation were found to be 14.14 ± 0.52% and 26.38 ± 0.27°, respectively.
In vitro dissolution studies
The release patterns of RT from SSDs and PMs are shown in [Figure 2]A–[D]. The order of drug release from SSDs was Gelucire 50/13 > PEG 6000 > PEG 4000. SSDs prepared from Gelucire 50/13 (SDG4) (99.84 ± 1.53% in 15 min) showed faster dissolution (significantly improved P < 0.05) than a marketed tablet (20.28 ± 1.84% in 15 min) and pure drug (11.95 ± 1.72% in 15 min). Dissolution enhancement of RT with Gelucire may be attributed to the emulsifying nature of Gelucire 50/13 and increased wettability., The increase in surface area of lactose monohydrate might also be contributed for the release of drug from SSD., The enhancement of dissolution was further confirmed by a significant increase in Q15, DE15%, and reduction in MDT [Table 5] for a formulation containing Gelucire 50/13 compared to marketed tablet and pure drug. The rates of drug release from PMs were also improved to a lesser extent compared to SSDs.
|Figure 2: (A) Comparison of in-vitro RT release from PEG 4000 formulations (n = 6). (B) Comparison of in-vitro RT release from PEG 6000 formulations (n = 6). (C) Comparison of in-vitro RT release from Gelucire 50/13formulations (n = 6). (D) Comparison of in-vitro RT release from various formulations (n = 6)|
Click here to view
|Table 5: Dissolution parameters of RT from various formulations (mean ± SD, n = 3)|
Click here to view
Dissolution data treatment
The dissolution data were analyzed further for DE and MDT. The results showed that a significant improvement in DE of RT from SSDs containing Gelucire 50/13 was 62.12% (SDG4 formulation) compared to marketed tablet (13.17%) and pure drug (5.24%) [Table 5]. A significant reduction in MDT of RT from SSDs containing Gelucire 50/13 (5.67 min) was observed compared to all other formulations, indicating faster release of drug and faster onset of action.
Characterization of SSD
FTIR spectra of SDG4 SSDs were compared with a plain drug, Gelucire 50/13, and PMG4 [Figure 3]. FTIR spectra of RT are characterized by 3263.65 cm−1 (N–H stretch of amide), 1773.54 cm−1 (C = O ester group of stretching), 1539.25 cm−1 (C = C aromatic group of stretching), and 1278.85 cm−1 (C–S stretching). PM (PMG4) also exhibits similar types of peaks. The absence of extra new peaks, the presence of all drug peaks in an optimized formulation (SDG4), suggests that interaction is absent between drug and Gelucire 50/13.
|Figure 3: Fourier transform infrared spectrum of a) RT b) Gelucire 50/13 c) PMG4 Physical mixture d) SDG4 optimized formulation|
Click here to view
Differential scanning calorimetry thermograms of RT showed an endothermic sharp peak at 81.76°C [Figure 4]A and Gelucire [Figure 4]B showed at 50.7°C corresponding to their melting points. In PM [Figure 4]C and optimized formulation [Figure 4]D, the peak was broadened, indicating molecular dispersion of drug in carrier.
|Figure 4: Differential scanning colorimeter thermograms of a) RT b) Gelucire 50/13 c) PMG4 physical mixture d) SDG4 optimized formulation|
Click here to view
[Figure 5] shows the X-ray diffractogram of plain RT, carrier, PMG4, and SDG4 formulation. The pattern of X-ray diffraction at 2θ angles of diffraction of RT showed sharp distinct peaks (i.e., 4°, 9°, 13°, 17°, 18°, and 20°) compared to less intense peaks in PMG4 and SDG4 formulation. The PM [Figure 5]C shows some intense peaks, indicating that the drug completely may not undergo solid-state transition. The peaks intensity was decreased or disappeared in SDG4 formulation [Figure 5]D, indicating a reduction in crystalline to amorphous drug form.
|Figure 5: X-ray diffraction patterns of a) RT b) Gelucire 50/13 c) PMG4 Physical mixture d) SDG4 optimized formulation|
Click here to view
SDG4 formulation was studied for stability according to ICH and stored for 6 months. No significant differences [Table 6] in drug release and drug content were observed between stored formulation and freshly prepared formulations, indicating the prepared formulations were stable for 6 months.
Mean RT plasma concentration profiles of SD with the surface adsorbent (formulation SDG4) and RT pure drug is showed in [Figure 6]. Various PK parameters are given in [Table 7]. Formulation SDG4 produced peak plasma concentration (Cmax) 65.38±1.34 µg/mL at Tmax of 0.5 h, in contrary to pure drug Cmax 37.29 ± 1.16 µg/mL at Tmax of 1 h. The AUC of SDG4 formulation was found to be 242.31 ± 3.65 µg-h/mL and that of pure drug was 134.45 ± 2.14 µg-h/mL, respectively. Percentage relative bioavailability of optimized formulation SDG4 was 180.22% in comparison to pure drug.
|Figure 6: In vivo plasma concentrations-time profile of SDG4 formulation and pure RT (n = 6)|
Click here to view
|Table 7: PK parameters of RT pure drug and SDG4 formulation (Avg ± SD n = 12)|
Click here to view
The decreased tmax with significant improvement in the Cmax of RT from SDG4 formulation compared to pure drug indicates a faster onset of action with improved dissolution and faster absorption rate. Similarly, significant improvement was observed in the AUC of optimized SDG4 formulation compared to pure drug. A significant change was observed in mean residence time of SDG4 (5.59 ± 0.14 h) and pure drug (4.65 ± 0.35 h). The faster onset of action is indicated with significant improvement in PK parameters (Cmax and AUC), enhanced dissolution, and faster absorption that resulted in bioavailability improvement of RT. Hence, the developed SD with surface adsorbent can be a choice for improving solubility, dissolution, and bioavailability of a poorly aqueous soluble drug, RT.
| Conclusion|| |
An effort was made to prepare SDs with surface adsorbents using polyethylene glycols and Gelucire as carrier to formulate RT SSDs, showing the faster drug release with improved flowable characteristics. The presence of Gelucire 50/13 showed significant enhancement of solubility and dissolution rate of poor aqueous soluble RT. In vivo bioavailability studies revealed that a considerable enhancement of oral bioavailability of RT from optimized SDG4 containing Gelucire 50/13 than pure drug. Thus, the use of SD with surface adsorbent is a promising method to promote the flow property, stability, and absorption of RT that improves the bioavailability of RT.
The authors are thankful to Gattefosse Private Limited and Symed Laboratory Limited for providing gift samples. The authors acknowledge Management, GITAM School of Pharmacy, GITAM Deemed to be university, Vagdevi College of Pharmacy and Sri Shivani College of Pharmacy for providing facilities for successful completion of work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Betageri GV, Makarla KR. Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. Int J Pharm 1995;126:155-60.
Bartsch SE, Griesser UJ. Physicochemical properties of the binary system glibenclamide and polyethylene glycol 4000. J Therm Anal Calorim 2004;77:555-69.
Six K, Leuner C, Dressman J, Verreck G, Peeters J, Blaton N, et al
. Thermal properties of hot-stage extrudates of itraconazole and Eudragit E100. Phase separation and polymorphism. J Therm Anal Cal 2002;68:591-601.
Urbanetz NA. Stabilization of solid dispersions of nimodipine and polyethylene glycol 2000. Eur J Pharm Sci 2006;28:67-76.
Ha NS, Tran TT, Tran PH, Park JB, Lee BJ. Dissolution-enhancing mechanism of alkalizers in poloxamer-based solid dispersions and physical mixtures containing poorly water-soluble valsartan. Chem Pharm Bull (Tokyo) 2011;59:844-50.
Karavas E, Georgarakis M, Docoslis A, Bikiaris D. Combining SEM, TEM, and micro-Raman techniques to differentiate between the amorphous molecular level dispersions and nanodispersions of a poorly water-soluble drug within a polymer matrix. Int J Pharm 2007;340:76-83.
Takeuchi H, Nagira S, Yamamoto H, Kawashima Y. Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method. Powder Technol. 2004;141:187-95.
Tran HT, Park JB, Hong KH, Choi HG, Han HK, Lee J, et al
. Preparation and characterization of pH-independent sustained release tablet containing solid dispersion granules of a poorly water-soluble drug. Int J Pharm 2011;415:83-8.
Gupta MK, Goldman D, Bogner RH, Tseng YC. Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent. Pharm Dev Technol 2001;6:563-72.
Chauhan B, Shimpi S, Paradkar A. Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. Eur J Pharm Sci 2005;26:219-30.
Williams AC, Timmins P, Lu M, Forbes RT. Disorder and dissolution enhancement: Deposition of ibuprofen on to insoluble polymers. Eur J Pharm Sci 2005;26:288-94.
Barzegar JM, Maleki N, Garjani A, Khandar AA, Hosseinloo HM, Jabbari R. Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique. Drug Dev Ind Pharm 2002;28:681-86.
Sharma S, Sher P, Badve S, Pawar AP. Adsorption of meloxicam on porous calcium silicate: Characterization and tablet formulation. AAPS Pharmscitech 2005;6:E618-25.
Chowdary KP, Rao SS. Investigation of dissolution enhancement of itraconazole by solid dispersion in superdisintegrants. Drug Dev Ind Pharm 2000;26:1207-11.
Derle DV, Pawar A, Patel JS, Rathi MN, Kothawade PI. Solubility enhancement of aceclofenac by solvent deposition method. Int J Pharm Tech Res 2010;2:843-46.
Rao M, Mandage Y, Thanki K, Bhise S. Dissolution improvement of simvastatin by surface solid dispersion technology. Dissolut Technol 2010;17:27-34.
Lindo ES, Ponce JS, Woo EC, Gutierrez M. Racecadotril in the treatment of acute watery diarrhea in children. N Engl J Med 2000;343:463-7.
Matheson AJ, Noble S. Racecadotril. Drugs 2000;59:829-35.
Cojocaru B, Bocquet N, Timsit S, Wille C, Boursiquot C, Marcombes F, et al
. [Effect of racecadotril in the management of acute diarrhea in infants and children]. Arch Pediatr 2002;9:774-9.
Alam NH, Ashraf H, Khan WA, Karim MM, Fuchs GJ. Efficacy and tolerability of racecadotril in the treatment of cholera in adults: A double blind, randomised, controlled clinical trial. Gut 2003;52:1419-23.
Primi MP, Bueno L, Baumer P, Berard H, Lecomte JM. Racecadotril demonstrates intestinal antisecretory activity in vivo. Aliment Pharmacol Ther 1999;13(Suppl 6):3-7.
Singh N, Narayan S. Racecadotril: A novel antidiarrheal. Med J Armed Forces India 2008;64:361-2.
Higuchi T, Connors K. Phase-solubility techniques. Adv Anal Chem Instrum 1965;7:117-212.
Bandari S, Jadav S, Eedara BB, Dhurke R, Jukanti R. Enhancement of solubility and dissolution rate of loratadine with gelucire 50/13. J Pharm Inn 2014;9:141-9.
Parmar KR, Shah SR, Sheth NR. Studies in dissolution enhancement of ezetimibe by solid dispersions in combination with a surface adsorbent. Dissolut Technol 2011;18:55-61.
Daravath B, Naveen CH, Vemula SK, Tadikonda RR. Solubility and dissolution enhancement of flurbiprofen solid dispersion using hydrophilic carriers. Braz J Pharm Sci 2017;53:1-10.
Chella N, Tadikonda R. Melt dispersion granules: Formulation and evaluation to improve oral delivery of poorly soluble drugs—a case study with valsartan. Drug Dev Ind Pharm 2015;41:888-97.
Daravath B, Tadikonda RR. Formulation and in vitro evaluation of flurbiprofen-polyethylene glycol 20000 solid dispersions. J App Pharm Sci 2014;4:76-81.
Chella N, Daravath B, Kumar D, Tadikonda RR. Formulation and pharmacokinetic evaluation of polymeric dispersions containing valsartan. Eur J Drug Metab Pharmacokinet 2016;41:517-26.
Mathews BR. Regulatory aspects of stability testing in Europe. Drug Dev Ind Pharm 1999;25:831-56.
Bhaskar D, Tadikonda RR. Formulation and evaluation of meclizine hydrochloride fast dissolving tablets using solid dispersion method. Asian J Pharm Clin Res 2014;7:98-102.
Prabhu SL, Singh T, Joseph A, Kumar CD, Shirwaikar A. Detarmination of racecadotril by HPLC in capsules. Indian J Pharm Sci 2007;69:819-21.
Daravath B, Tadikonda RR, Vemula SK. Formulation and pharmacokinetics of gelucire solid dispersions of flurbiprofen. Drug Dev Ind Pharm 2015;41:1254-62.
Alladi S, Shastri NR. Semi solid matrix formulations of meloxicam and tenoxicam: An in vitro and in vivo evaluation. Arch Pharm Res 2015;38:801-12.
Chambin O, Jannin V. Interest of multifunctional lipid excipients: Case of gelucire 44/14. Drug Dev Ind Pharm 2005;31:527-34.
da Fonseca Antunes AB, De Geest BG, Vervaet C, Remon JP. Gelucire 44/14 based immediate release formulations for poorly water-soluble drugs. Drug Dev Ind Pharm 2013;39:791-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]