Dissolution

Title

Kinetics of drug release from ointments: Role of transient-boundary layer

 

Authors

Xiaoming Xu, Manar Al-Ghabeish, Yellela S.R. Krishnaiah, Ziyaur Rahman, Mansoor A. Khan

Abstract

In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time.

 

Publication

International Journal of Pharmaceutics

 

Bibliography

Xu, X.; Al-Ghabeish, M.; Krishnaiah, Y.; Rahman, Z.; Khan, M. Kinetics of drug release from ointments: Role of transient-boundary layer. Int J Pharm. 2015 Oct 15;494(1):31-9.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/26241753

 

 

 

 

Title

Novel oral formulation approach for poorly water-soluble drug using lipocalin-type prostaglandin D synthase

 

Authors

Masashi Mizoguchi, Masatoshi Nakatsuji, Haruka Inoue, Keisuke Yamaguchi, Atsushi Sakamoto, Koichi Wada, Takashi Inui

 

Abstract

Lipocalin-type prostaglandin D synthase (L-PGDS), a member of the lipocalin superfamily, possesses the function of forming complexes together with various small lipophilic molecules. In this study, we chose telmisartan as a model drug due to its pH dependent poor water solubility, and developed and characterized a novel solubilized formulation of telmisartan using a complex formulation with L-PGDS. The solid state of the complex formulation was prepared using a spray-drying process. The spray-dried formulation of telmisartan/L-PGDS powder showed a typical spray-dried particle without any change in the secondary and tertiary structures of L-PGDS. Furthermore, the complex formulation showed a high rate and level of drug release in pH 1.2, 5.0, and 6.8 solutions in comparison with the active pharmaceutical ingredient (API) and commercial product. To validate the potential for oral administration of the telmisartan/ L-PGDS complex in vivo, the pharmacokinetic and pharmacodynamic profiles were assessed in spontaneous hypertensive rats. An animal study revealed that the complex formulation led to a significant improvement of AUC and Cmax as compared with API, and the prolonged pharmacologic effect on blood pressure reduction was comparable with the commercial product. These results, taken together, demonstrate that this novel approach is feasible for the solubilized solid oral formulation and it can be applied to poorly water-soluble drugs to enhance oral bioavailability.

 

Publication

European Journal of Pharmaceutical Sciences

 

Bibliography

Mizoguchi, M.; Nakatsuji, M.; Inoue, H.; Yamaguchi, K.; Sakamoto, A.; Wada, K.; Inui, T. Novel oral formulation approach for poorly water-soluble drug using lipocalin-type prostaglandin D synthase. Eur J Pharm Sci. 2015 Jul 10; 74:77–85.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/25906910

 

 

 

 

Title

Formulation and development of pH-independent/dependent sustained release matrix tablets of ondansetron HCl by a continuous twin-screw melt granulation process

 

Authors

Hemlata Patil, Roshan V. Tiwari, Sampada B. Upadhye, Ronald S. Vladyka, Michael A. Repka

 

Abstract

The objective of the present study was to develop pH-independent/dependent sustained release (SR) tablets of ondansetron HCl dihydrate (OND), a selective 5-HT3 receptor antagonist that is used for prevention of nausea and vomiting caused by chemotherapy, radiotherapy and postoperative treatment. The challenge with the OND API is its pH-dependent solubility and relatively short elimination half-life. Therefore, investigations were made to solve these problems in the current study. Formulations were prepared using stearic acid as a binding agent via a melt granulation process in a twin-screw extruder. The micro-environmental pH of the tablet was manipulated by the addition of fumaric acid to enhance the solubility and release of OND from the tablet. The in vitro release study demonstrated sustained release for 24 h with 90% of drug release in formulations using stearic acid in combination with ethyl cellulose, whereas 100% drug release in 8 h for stearic acid-hydroxypropylcellulose matrices. The formulation release kinetics was correlated to the Higuchi diffusion model and a non-Fickian drug release mechanism. The results of the present study demonstrated for the first time the pH dependent release from hydrophilic-lipid matrices as well as pH independent release from hydrophobic-lipid matrices for OND SR tablets manufactured by means of a continuous melt granulation technique utilizing a twinscrew extruder.

 

Publication

International Journal of Pharmaceutics

 

Bibliography

Patil, H.; Tiwari, R.V.; Upadhye, S.b.; Vladyka, R.S.; Repka, M.A. Formulation and development of pH-independent/dependent sustained release matrix tablets of ondansetron HCl by a continuous twin-screw melt granulation process. Int J Pharm. 2015 Dec 30; 496(1):33–41.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/25863118

 

 

 

 

Title

Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro–in vivo evaluations

 

Authors

Manjeet B. Pimparade, Joseph T. Morott, Jun-Bom Park, Vijay I. Kulkarni, Soumyajit Majumdar, S.N. Murthy, Zhuoyang Lian, Elanor Pinto, Vivian Bi, Thomas Durig, Reena Murthy, Shivakumar H.N, K. Vanaja, Kumar P C., Michael A. Repka

 

Abstract

The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30 min in 0.1 N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly.

 

Publication

International Journal of Pharmaceutics

 

Bibliography

Pimparade, M.B.; Morott, J.T.; Park, J.; Kulkarni, V.I.; Majumdar, S.; Murthy, S.N.; Lian, Z.; Pinto, E.; Bi, V.; Durig, T.; Murthy, R.; Shivakumar, H.N.; Vanaja, K.; Kumar, P.C.; Repka, M.A. Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro–in vivo evaluations. Int J Pharm. 2015 Jun 20;487(1-2):167-76.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/25888797

 

 

 

 

Title

Crystal Structure and Physicochemical Characterization of Ambazone Monohydrate, Anhydrous, and Acetate Salt Solvate

 

Authors

Marieta Muresan-Pop, Dario Braga, Mihaela M. Pop, Gheorghe Borodi, Irina Kacso, Lucia Maini

 

Abstract

The crystal structures of the monohydrate and anhydrous forms of ambazone were determined by single-crystal X-ray diffraction (SC-XRD). Ambazone monohydrate is characterized by an infinite three-dimensional network involving the water molecules, whereas anhydrous ambazone forms a two-dimensional network via hydrogen bonds. The reversible transformation between the monohydrate and anhydrous forms of ambazone was evidenced by thermal analysis, temperature-dependent X-ray powder diffraction and accelerated stability at elevated temperature, and relative humidity (RH). Additionally, a novel ambazone acetate salt solvate form was obtained and its nature was elucidated by SC-XRD. Powder dissolution measurements revealed a substantial solubility and dissolution rate improvement of acetate salt solvated form in water and physiological media compared with ambazone forms. Also, the acetate salt solvate displayed good thermal and solution stability but it transformed to the monohydrate on storage at elevated temperature and RH. Our study shows that despite the requirement for controlled storage conditions, the acetate salt solvated form could be an alternative to ambazone when solubility and bioavailability improvement is critical for the clinical efficacy of the drug product.

 

Publication

Journal of Pharmaceutical Sciences

 

Bibliography

Muresan-Pop, M.; Braga, D.; Pop, M.M.; Borodi, G.; Kacso, I.; Maini, L. Crystal Structure and Physicochemical Characterization of Ambazone Monohydrate, Anhydrous, and Acetate Salt Solvate. J Pharm Sci. 2014 Nov;103(11):3594-601.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/25187325

 

 

 

 

Title

Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs

 

Authors

Sara B.E. Andersson, Caroline Alvebratt, Jan Bevernage, Damien Bonneau, Claudia da Costa Mathews, Rikesh Dattani, Khadijah Edueng, Yan He, Rene Holm, Cecilie Madsen, Thomas Müller, Uwe Muenster, Anette Müllertz, Krista Ojala, Thomas Rades, Peter Sieger, Christel A.S. Bergstr€om

 

Abstract

The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolutionwas studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelineswere established: for compounds with Sapp > 1 mg/mL, the disc method is recommended. Forcompounds with Sapp<100 mg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 mg/mL to 1 mg/mL can be analyzed with either of these methods.

 

Publication

Journal of Pharmaceutical Sciences

 

Bibliography

Andersson, S.B.E.; Alvebratt, c.; Bevernage, J.; Bonneau, D.; da Costa Mathews, C.; Dattani, R.; Edueng, K.; He, Y.; Holm, R.; Madsen, C.; Müller, T.; Muenster, U.; Müllertz, A.; Ojala, K.; Rades, T.; Sieger, P.; Bergström, C.A.S. Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs. J Pharm Sci. September 2016. Volume 105, Issue 9, Pages 2864–2872.

 

Link

http://jpharmsci.org/article/S0022-3549(16)00438-X/fulltext

 

 

 

 

Title

Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs

 

Authors

K. Tsinman, A. Avdeef, O. Tsinman, D. Voloboy

 

Abstract

PURPOSE: The objective was to investigate the applicability and limitations of a novel approach for measuring intrinsic dissolution rates (IDR) of very small quantities of compounds introduced as powders to buffered solutions and comparing these results to disk IDR obtained using the traditional Wood's apparatus.

 

METHODS: The powder dissolution profiles of 13 model drugs were determined at 37 degrees C in USP buffers at pH 1.2, 4.5, and 6.8, stirred at 100 RPM. As little as 0.06 mg of drug were added to 1 mL buffer media. Drug concentration was measured by an in situ fiber optic UV method. The results were converted to rotating disk IDR values by a novel mathematical procedure.

 

RESULTS: The comparison of the powder-based IDR values to those obtained by traditional Wood's apparatus indicated r(2) = 0.97 (n = 26).

 

CONCLUSION: The results demonstrate that using potentially 10,000-fold less drug material does not sacrifice the quality of the measurement, and lends support to an earlier study that the disk IDR measurement may possibly serve as a surrogate for the BCS solubility classification.

 

Publication

Pharmaceutical Research

 

Bibliography

Tsinman, K.; Avdeef, A.; Tsinman, O.; Voloboy, D. Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs. Pharm Res. 2009 Sep;26(9):2093-100. (Part 5 in the μDISS Series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/19543816

 

 

 

 

Title

Miniaturization of Powder Dissolution Measurement and Estimation of Particle Size

 

Authors

A. Avdeef, K. Tsinman, O. Tsinman, N. Sun, D. Voloboy

 

Abstract

The objective was to investigate the applicability and limitations of an approach for estimating particle size from powder dissolution measurement using as little as 50 microg of sample in 1 ml of buffer solutions. The powder dissolution profiles of five sparingly-soluble drugs (hydrochlorothiazide, phenazopyridine hydrochloride, 2-naphthoic acid, indomethacin, and dipyridamole) were evaluated with a novel biexponential spherical particle equation and also the Wang-Flanagan spherical particle non-sink equation. The results were compared to particle sizing based on measured specific surface area by the Brunauer-Emmett-Teller (BET) method, and also based on Coulter counting. With the exception of hydrochlorothiazide, the model compounds indicated some agglomeration in the dissolution media. The dry-state specific surface area was larger than expected from either the Coulter method or the powder-dissolution data, especially for phenazopyridine hydrochloride. The particle radii estimated by the powder dissolution method ranged from 10 to 68 microm, with equilibrium solubilities spanning from 5 microg/ml (dipyridamole) to 911 microg/ml (hydrochlorothiazide). Powder dissolution data collected with the miniaturized apparatus can be used to determine particle size, with estimated values agreeing reasonably with those measured by the Coulter counter method.

 

Publication

Chemistry & Biodiversity

 

Bibliography

Avdeef, A.; Tsinman, K.; Tsinman, O.; Sun, N.; Voloboy, D. Miniaturization of Powder Dissolution Measurement and Estimation of Particle Size. Chem Biodivers. 2009 Nov; 6(11):1796-811. (Part 6 in the μDISS Series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/19937817

 

 

 

 

Title

Miniaturized rotating disk intrinsic dissolution rate measurement: effects of buffer capacity in comparisons to traditional Wood’s apparatus

 

Authors

A. Avdeef, O. Tsinman

 

Abstract

PURPOSE: The objective was to investigate the feasibility of using a miniaturized disk intrinsic dissolution rate (IDR) apparatus to determine the Biopharmaceutics Classification System (BCS) solubility class, and to develop an approach where IDR measurements performed in media of different buffer capacity could be compared.

 

METHODS: The disk IDR values of 14 model drugs were determined at 37 degrees C in US Pharmacopeia buffers at pH 1.2, 4.5, and 6.8. As little as 5 mg of drug were compressed in a die, with surface area of 0.071 cm(2), with the die assembly rotated at 100 rpm in 10 mL media. Drug concentration was measured by an in situ fiber optic ultraviolet method. The solubilities and pK(a)s were determined, and used to simulate dissolution profiles with a convective-diffusion-with-chemical-reaction model.

 

RESULTS: The disk IDR values spanned six orders of magnitude (0.00014 to 114 mg min(-1) cm(-2)). The comparison of the miniaturized disk IDR values to published results using traditional dissolution bath apparatus indicated r (2) = 0.99.

 

CONCLUSIONS: The results demonstrate that using 100-fold less drug does not sacrifice the quality of the measurement, and lends support to an earlier study Yu et al. (Int. J. Pharm. 270:221-227, 2004) that the disk IDR measurement may possibly serve as a surrogate for the BCS solubility classification.

 

Publication

Pharmaceutical Research

 

Bibliography

Avdeef, A.; Tsinman, O. Miniaturized rotating disk intrinsic dissolution rate measurement: effects of buffer capacity in comparisons to traditional Wood’s apparatus. Pharm Res. 2008 Nov; 25(11):2613-27. (Part 4 in the μDISS Series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/18648912

 

 

 

 

Title

Miniaturized Intrinsic Dissolution Rate (Mini-IDR™) Measurement of Griseofulvin and Carbamazepine

 

Authors

CM Berger, O Tsinman, D Voloboy, D Lipp, S Stones, A Avdeef

 

Abstract

Griseofulvin and carbamazepine were selected as model drugs to compare measurements of disk intrinsic dissolution rate (IDR) by a traditional (Wood apparatus) USP method (500-mg pellet, 900 mL media) and a new miniaturized method (5-mg pellet, 15 mL media) at 37 °C and 100 rpm. An in situ fiber optic UV instrument was used to collect dissolution data, with IDR calculated and displayed in real time. The IDR values from the present study and those reported by an FDA group (1) agree well, suggesting that the scale-down of hydrodynamics may be a reliable option for early development studies, where quantities of API are often highly limited.

 

Publication

Dissolution Technologies

 

Bibliography

Berger, CM.; Tsinman, O.; Voloboy, D.; Lipp, D.; Stones, S.; Avdeef, A. Miniaturized Intrinsic Dissolution Rate (Mini-IDR™) Measurement of Griseofulvin and Carbamazepine. Dissolut .Tech. 2007, 14, 39-41. (Part 3 in the μDISS Series)

 

Link

http://www.dissolutiontech.com/DTresour/200711Articles/DT200711_A05.pdf

 

 

 

 

Title

Dissolution and Solubility (in Comprehensive Medicinal Chemistry II, Vol. 5)

 

Authors

A. Avdeef, D. Voloboy, A. Foreman

 

Publication

Comprehensive Medicinal Chemistry II, Vol. 5

 

Bibliography

Avdeef, A.; Voloboy, D.; Foreman, A. Dissolution and Solubility. In: Testa, B.; van de Waterbeemd, H. (Eds.). Comprehensive Medicinal Chemistry II, Vol. 5 ADME-TOX Approaches. Elsevier: Oxford, UK, 2007, pp. 399-423. (Part 1 in μDISS series)

 

Link

http://www.sciencedirect.com/science/referenceworks/9780080450445

 

 

 

 

Title

In situ fiber optic dissolution monitoring of vitamin B12 solid dosage formulation

 

Authors

CJ Toher, PE Nielsen, AS Foreman, A Avdeef

 

Abstract

The rapid dissolution rate of many water-soluble, immediate release solid dosage forms requires a dissolution analyzer that is fast, sensitive, customizable for frequent measurements, and able to generate data of high precision and quality. These requirements fit perfectly with today’s in situ fiber optic technology. The Rainbow Dynamic Dissolution Monitor was used in this study to demonstrate and evaluate the dissolution behavior of 500 mg Vitamin B12 (cyanocobalamin) tablets in degassed water, simulated gastric fluid (SGF), and phosphate buffer at stirring speeds as high as 100 rpm. Upon dissolution, Vitamin B12 tablets produce rather turbid suspensions that may be expected to cause problems for in situ measurements. However, the effect of light scattering by suspensions is largely eliminated when the second derivative of the absorbance signal is used in quantitation. Excellent data correlation was observed between the different media and the standard when using this method.

 

Publication

Dissolution Technologies

 

Bibliography

Toher, CJ.; Nielsen, PE.; Foreman, AS.; Avdeef, A. In situ fiber optic dissolution monitoring of vitamin B12 solid dosage formulation. Dissol. Technol. 2003, 10, 20-25.

 

Link

http://www.dissolutiontech.com/DTresour/200311Articles/DT200311_A03.pdf

 

 

 

 

Title

Dissolution Rate and Apparent Solubility of Poorly Soluble Compounds in Biorelevant Dissolution Media

 

Author

JH Fagerberg, O Tsinman, K Tsinman, N Sun, A Avdeef, CAS Bergström

 

Abstract

A series of poorly soluble BCS class II compounds with "grease ball" characteristics were assessed for solubility and dissolution rate in biorelevant dissolution media (BDM) with the purpose of investigating which molecular structures gain most in solubility when dissolved under physiologically relevant conditions. The compounds were studied in four media (simulated intestinal fluid in fasted (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0), and their corresponding blank buffers (FaSSIF(blk) and FeSSIF(blk))) at a temperature of 37 °C. The experimental results were used to analyze which molecular characteristics are of importance for the solubility in BDM and for in silico modeling using multivariate data analysis. It was revealed that a majority of the compounds exhibited a higher dissolution rate and higher solubility in the FaSSIF and FeSSIF than in their corresponding blank buffers. Compounds which were neutral or carried a positive charge were more soluble in FeSSIF than FaSSIF. The acidic compounds displayed clear pH dependency, although the higher concentration of solubilizing agents in FeSSIF than FaSSIF also improved the solubility. Five of the ten compounds were upgraded to BCS class I when dissolved in FaSSIF or FeSSIF, i.e., the maximum dose of these compounds given orally was soluble in 250 mL of these BDMs. Lipophilicity as described by the log D(oct) value was identified as a good predictor of the solubilization ratio (R(2) = 0.74), and computed molecular descriptors were also shown to successfully predict the solubilities in BDM for this data set. To conclude, the physiological solubility of "grease ball" molecules may be largely underestimated in in vitro solubility assays unless BDM is used. Moreover, the results herein indicate that the improvement obtained in BDM may be possible to predict from chemical features alone.

 

Publication

Molecular Pharmaceutics

 

Bibliography

Fagerberg, JH.; Tsinman, O.; Tsinman, K.; Sun, N.; Avdeef, A.; Bergström, CAS. Dissolution Rate and Apparent Solubility of Poorly Soluble Compounds in Biorelevant Dissolution Media. Mol Pharm. 2010 Oct 4;7(5):1419-30. (Part 7 in the μDISS Series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/20507160