Dissolution Kinetics Of Drugs Research Articles

Solid Dispersions: An Effective Technology for Improving Dissolution Kinetics of Poorly Soluble Drugs

Solid dispersions are one of the essential technologies for improving solubility and dissolution kinetics of drugs. They can be prepared in several ways and using different carriers. This technique is very suitable for class II BCS drugs, one of which is mefenamic acid. This paper is devoted to improving the solubility and dissolution rate of mefenamic acid by preparing solid dispersions using polyethylene glycol 4000, polyvinylpyrrolidone K30, and polysorbate 80 as carriers. Solid dispersions were prepared by kneading method, and dissolution was studied for two hours in phosphate buffer (pH=8). Experimental data of drug release from prepared solid dispersions were analysed according to different mathematical models. The results showed that the dissolution rate varied depending on the type and fraction of the carrier. However, mefenamic acid was released from all prepared formulations in accordance with the Higuchi model, and the release mechanism was better described by Fickian diffusion.

Adding a New Dimension to the Amorphous Solid Dispersion Phase Diagram: Studying Dissolution Kinetics of Crystalline Drugs in a Polymer Matrix Using Temperature Dependent XRPD and DSC

Hot-melt-extrusion (HME) is an enabling technology used for poorly soluble active pharmaceutical ingredients (APIs) to increase the bioavailability by embedding the drug in a water soluble and often amorphous carrier such as a polymer. Knowledge of the most critical factors impacting the dissolution rate of crystalline API in the polymer during manufacturing will provide useful insight for process improvement. In this study, crystalline APIs (Acetaminophen, APAP and Indomethacin, IMC) were analyzed in a polymeric matrix (Copovidone, PVP-VA64) via X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) to follow the dissolution process under various conditions in a down-scaled static laboratory system. The combination of in-situ XRPD measurements and a kinetic model based on DSC data proved to be a suitable tool to investigate the dissolution process and can be applied to various APIs and polymers to avoid residual crystallinity and thermal degradation. Thus, the temperature-composition phase diagram in a thermodynamic equilibrium is augmented by the kinetic component as new dimension. The obtained findings set the foundation for investigating the dissolution kinetics and enable the transition from a static to a dynamic system.

Study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro

Atorvastatin and lisinopril are a successful combination for the treatment of patients with chronic heart failure and hypertension. Study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro were described. In medium with hydrochloric acid pH 1.2, in the medium of acetate buffer solution with a pH of 4.5 and in the medium phosphate buffer solution with a pH of 6.8 for 15 min more than 85% of the active substance passes into solution, hence the dissolution profiles these drugs in these environments are similar, and the drugs in them are “very quickly soluble”. Among the in vitro models that make it possible to assess the degree of absorption of API, the most widely used culture of adenocarcinoma cells of the colon – Caco-2. The development of the analytical methodology and its validation is the final stage of both the dissolution study and the Caco-2 test, as well as the biowaver procedure. It plays the most important role in the reliability of the results for all the above procedures and tests. To study permeability, method LC-MS/MS was developed. According to the obtained results, atorvastatin and lisinopril showed low permeability. The values ​​of recovery of transport of test and control substances through the monolayer of cells of the Caco-2 line indicate that the results of the experiment can be considered reliable. The equivalence of the drugs “Lisinopril”, tablets of 10 mg and “Atorvastatin”, tablets of 10 mg, belongs to class III BCS proven by in vitro studies.

Alternative Methods for Dissolution Profile Comparison in the Dissolution Test

Introduction. The article discusses the problem of assessing the similarity of the dissolution profiles of two batches of the nebivolol. The use of a generally accepted similarity factor for assessing equivalence is unacceptable in some cases, for example, for drugs with a high variability in the values of the release of the active substance from the formulation. At the same time, at present, there are no generally accepted approaches to comparing the profiles of the dissolution kinetics of drugs, with the exception of the method for assessing the comparability of profiles based on the mathematical calculation of the similarity factor f2, which has certain criteria that limit its application.Aim. To demonstrate alternative methods for assessing the similarity between the dissolution profiles of two drugs using a practical example.Materials and methods. The results of the comparative dissolution test of two series of nebivolol at a dosage of 5 mg. Five model-independent methods for assessing the equivalence of drug dissolution were used. Statistical data processing was performed using Microsoft Excel software.Results and discussion. The paper presents a practical example of using five alternative model-independent methods for assessing the equivalence of the dissolution profile. An example is used to illustrate the proposed equivalence limits and statistical methodology. Also, various approaches to determining the boundaries of equivalence have been proposed to assess the similarity of the dissolution profiles of an active substance.Conclusion. According to the results of the comparative dissolution test of two batches of nebivolol, it was shown that the use of the similarity factor as a criterion for assessing dissolution profiles led to a false positive result. In such cases, the possibility of using alternative methods for assessing the equivalence of dissolution profiles described in the article, or other methods presented in the scientific literature, should be considered, with a justification of their acceptability in each specific case.

Comparative studies of the kinetics of dissolution of medicines on the basis of clopidogrel

Generic medicines occupy dominant positions both in the pharmaceutical market of Ukraine and in industrial production by domestic pharmaceutical enterprises. The use of generic drugs in medical practice is of significant medical and social importance for expanding the accessibility of the general population to essential drugs. In Ukraine, more than twenty generic medicines based on clopidogrel, both foreign and domestic, are registered. All generic drugs containing clopidogrel bisulfate must comply with pharmaceutical bisulfate must comply with pharmaceutical equivalence, the kinetics of release of the active pharmaceutical ingredient using the Dissolution test in vitro, and pharmacokinetic parameters in vivo.
 The aim of the work was to carry out comparative studies of the dissolution kinetics of four samples of generic drugs based on clopidogrel with the dissolution kinetics of the original drug Plavix®, to evaluate the similarity factor of dissolution profiles and to determine the effect of biopharmaceutical factors on the equivalence of generics. Comparative studies of the kinetics of dissolution were carried out by the in vitro method according to the «Dissolution» test using a device with a blade with a
 rotation speed of 50 rpm, a dissolution medium with a pH value of 2.0 in a volume of 900 ml at a temperature of 37 ± 1 °C. The determination of the quantitative content of clopidogrel, which passed into the dissolution medium, was carried out by the method of adsorption spectrophotometry in the ultraviolet region at a wavelength of
 about 240 ± 2 nm. Based on the data obtained, the dissolution profiles of the original drug Plavix® and the studied samples of generic drugs were constructed, the similarity of which was assessed by the value of the similarity factor. According to the research results, it was found that one sample of the generic drug proved its equivalence by the in vitro method to Plavix®, and three other samples of generics had differences in dissolution kinetics in comparison with the original drug. Biopharmaceutical factors were analyzed that could affect the dissolution kinetics of the studied generic drugs, from which the physicochemical characteristics of clopidogrel bisulfate, the qualitative and quantitative composition of excipients and the features of the technological process were determined.
 Thus, on the basis of the comparative studies of the dissolution kinetics of drugs based on clopidogrel, generics were found that did not correspond to the in vitro equivalence according to the Dissolution test to the original drug, which could be due to the influence of a combination of biopharmaceutical factors.

Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring.

The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.

HPLC method development and in vitro dissolution kinetics of amlodipine tablets under biowaiver conditions

A biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (not considered necessary for product approval). Instead of conducting expensive and time consuming in vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether the two pharmaceutical products are equivalent. The biowaiver approach based on BCS is intended to replace bioequivalence in vivo studies. The aim of the study was to study dissolution kinetics of amlodipine tablets in order to assess their equivalence under conditions in vitro according to the biowaiver. The study of dissolution kinetics of drugs in the form of amlodipine tablets has been carried out in accordance with the requirements of the “biowaiver” procedure, the recommendations of the SPhU and the WHO requirements in order to assess the possibility of replacing the pharmacokinetic studies in vivo by tests in vitro. The possibility to use the recommendations of the "biowaiver" procedure for the registration of generics amlodipine tablets has been found. The studies conducted have shown that amlodipine can be referred to class І of the biopharmaceutical classification system, i.e. substances with a high biopharmaceutical solubility and a high penetration rate. It will allow conducting comparative studies in vitro to confirm the equivalence of drugs. The evaluated amlodipine drugs fulfill biowaiver criteria for drugs containing BCS Class I active pharmaceutical ingredients. Both drugs are “rapidly dissolving,” both meet the criteria of dissolution profile similarity, f2 (i.e., the dissolution profile of the test product is similar to that of the reference product in pH 1.2, 4.5, and 6.8 buffers using the paddle method at 75 rpm), and both are considered to be in vitro equivalent without in vivo evaluation. The proposed chromatographic methods are simple, rapid and accurate for the determination of amlodipine in pharmaceutical dosage forms and can be used for routine quality control of drugs and in vitro dissolution study.

Low Energy Nanoemulsions as Templates for the Formulation of Hydrophobic Drugs

AbstractMost small molecule active pharmaceutical ingredients (APIs) are hydrophobic which poses formulation challenges due to their poor water solubility. Current approaches are energy intensive and involve presenting the API in a nanoparticle form that is then combined with other additives into a stable formulation. Here, a bottom‐up and scalable method that formulates nanoparticles (crystalline or amorphous) of poorly water‐soluble APIs directly embedded in composite hydrogel beads is presented. Using nanoemulsions prepared from a low energy method as templates, the flexible approach allows to vary the embedded API nanoparticle size from 100 to 500 nm and the hydrogel bead size from 100 to 1200 µm, and subsequently achieve control over the dissolution kinetics. To better understand the dissolution process, a physical model is build that allows to collapse the kinetic data onto a master curve and predict the dependence of release rates on size of both API nanoparticles and hydrogel beads. Lastly, it is demonstrated that the dissolution kinetics of multiple drugs embedded in the same hydrogel matrix can be tuned simultaneously, an attractive property for commercial multi‐drug dosage applications. The new approach not only leads to process intensification, but also improved performance.

Modeling the influence of cyclodextrins on oral absorption of low solubility drugs: II. Experimental validation

A model was developed for predicting the influence of cyclodextrins (CDs) delivered as a physical mixture with drug on oral absorption. CDs are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. The purpose of this work is to compare the simulation predictions with in vitro as well as in vivo experimental results to test the model's ability to capture the influence of CD on key processes in the gastrointestinal (GI) tract environment. Dissolution and absorption kinetics of low solubility drugs (Naproxen and Nifedipine) were tested in the presence and absence of CD in a simulated gastrointestinal environment. Model predictions were also compared with in vivo experimental results (Glibenclamide and Carbamazepine) from the literature to demonstrate the model's ability to predict oral bioavailability. Comparisons of simulation and experimental results indicate that a model incorporating the influence of CD (delivered as a physical mixture) on dissolution kinetics and binding of neutral drug can predict trends in the influence of CD on bioavailability. Overall, a minimal effect of CD dosed as a physical mixture was observed and predicted. Modeling may aid in enabling rational design of CD containing formulations.

Dissolution kinetics of unstable drugs in two-compartment autoinjectors: Analysis of the individual shaking behaviour and influence of various shaking parameters on the dissolution rate of HI 6 in an automated system

Despite the ubiquitous use of multi-phase drug formulations, detailed investigations on the dispersion kinetics upon shaking are apparently lacking. We were faced with these problems when analysing the operational function of newly developed autoinjectors containing a pharmaceutically unstable nerve agent antidote formulation. For the immediate treatment of organophosphate poisoning, dry/wet autoinjectors have been developed, containing the broad-spectrum cholinesterase reactivator HI 6 dichloride as a powder and atropine in solution. After breaking a separating membrane, HI 6 has to be dissolved by shaking for 5 s prior to injection. Although being crucial for quick dissolution, the mode of shaking has been poorly specified by the two manufacturers. After recording the individual shaking behaviour of 50 volunteers, we constructed a shaking apparatus allowing the imitation of the spontaneous human shaking motion. Mockups of both autoinjector chambers with pneumatic activation, programmed shaking and ejection of the suspension through a filter allowed us to analyse the dissolution progress within seconds. The results with HI 6 dichloride at 5°C showed that complete dissolution was not achieved within 5 s. The dissolution rate was dependent on shaking frequency, height of stroke, inclination of the shaking axis, and the dimensions of the mockups. Upon vertical shaking, a threshold frequency was observed above which the dissolution rate increased abruptly. Horizontal shaking accelerated the dissolution rate and the threshold frequency could be lowered considerably. While HI 6 dichloride did not allow complete dissolution at 5°C, HI 6 dimethanesulphonate was completely dissolved in less than 5 s under shaking conditions as observed with more than 75% of the untrained volunteers.

Aluminum-27 nuclear magnetic resonance spectroscopy and imaging of the human gastric lumen.

Aluminum NMR is proposed as a new imaging and spectroscopy modality. Its potential is exemplified by in vivo studies of the human stomach. The dissolution kinetics of aluminum-containing drugs at physiological doses and their removal from the human stomach have been followed by 27Al magnetic resonance spectroscopy (MRS). Aluminum concentrations as low as 0.5 mg Al3+ in the human stomach can be detected. The time course of gastric emptying has been visualized with 27Al magnetic resonance imaging (MRI) under normal conditions and in the presence of an antimuscarinic agent, which reduces the gastric motor function. 27Al MRI is the only direct method to visualize the gastric pH. 27Al MRI opens new possibilities for medical and pharmaceutical science.

Dissolution of ionizable drugs in buffered and unbuffered solutions.

The dissolution kinetics of ionizable drugs (weak acids or bases) are analyzed with a mathematical model derived from the theory of mass transfer with chemical reaction. The model assumes that the overall process is diffusion limited, that all the reactions are reversible and instantaneous, and that dissolution and reaction are limited to the stagnant fluid film adjacent to the solid phase. Dissolution into buffered and unbuffered aqueous solutions are considered separately, with convenient analytical solutions obtained in both cases. In addition, equations for the time to partial and complete dissolution are derived. The dissolution rate is shown to be dependent on the pKa and intrinsic solubility and the medium properties, i.e., pH, buffer capacity, and mass transfer coefficient. Equations of a form analogous to the nonionized case are derived to account explicitly for all these factors, with dissolution rates expressed in terms of the product of a driving force (concentration difference) and resistance (inverse of mass transfer coefficient). The solutions are in an accessible analytical form to calculate the surface pH and subsequently the surface concentrations driving the drug dissolution. Numerical examples to illustrate dissolution into unbuffered and buffered media are presented and the results are shown to be in accord with experimental data taken from the literature.

Program for evaluating drug dissolution kinetics in preformulation.

The in vitro dissolution kinetics of various drugs were studied at different experimental conditions using both a centrically rotating disc method and a modified excentrically rotating disc method. The combination of these two methods provides a preformulation program that includes many important pharmaceutical and biopharmaceutical parameters related to drug dissolution. The influence of the hydrodynamic conditions on the dissolution rate was demonstrated and the intrinsic dissolution tendency was obtained. Further, the acid dissociation constant, diffusion coefficient and enthalpy of dissolution can be calculated from data obtained from the rotating disc experiments. The relationship between dissolution rate and aqueous solubility of each drug tested is also considered.

Automated Potentiometric Procedure for Studying Dissolution Kinetics of Acidic Drugs under Sink Conditions

An automated potentiometric procedure was used for studying in vitro dissolution kinetics of acidic drugs. Theoretical considerations indicated that the pH-stat method could be used to establish approximate sink conditions or, possibly, a perfect sink. Data obtained from dissolution studies using the pH-stat method were compared with data obtained from known sink and nonsink conditions. These comparisons indicated that the pH-stat method can be used to establish a sink condition for dissolution studies. The effective diffusion layer thicknesses for benzoic and salicylic acids dissolving in water were determined, and a theoretical dissolution rate was calculated utilizing these values. The close agreement between the experimental dissolution rates obtained under pH-stat conditions and the theoretical dissolution rates indicated that perfect sink conditions were established under the experimental conditions used.

Dissolution Kinetics of Drugs in Human Gastric Juice—The Role of Surface Tension

The kinetics of in vitro dissolution of phenacetin and phenobarbital in human gastric juice have been determined and compared to those in hydrochloric acid containing various amounts of polysorbate 80. The surface tension of the dissolution medium is shown to have an appreciable effect on the dissolution kinetics of the drugs studied.