Solubility and dissolution profile assessment in drug discovery

The purposes of the review are to: a) Provide a comprehensible introduction of the-state-of-the-art sciences of solubility and dissolution, b) introduce typical technologies to assess solubility and dissolution, and c) propose the best practice strategy. The theories of solubility and dissolution required in drug discovery were reviewed especially from the view point of oral absorption. The physiological conditions in the gastrointestinal fluid in humans and animals were then briefly summarized. Technologies to assess solubility and dissolution in drug discovery were then introduced. Recently, these technologies have been improved by the laboratory automation and computational technologies. Finally, the strategies to apply these technologies for a drug discovery project were discussed.     

Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound

The usefulness of selected biorelevant dissolution media (BDM) to predict in vivo drug absorption was studied. Dissolution profiles of solid formulations of a poorly soluble model compound were compared in BDM simulating fasted and two levels of fed state. A non-physiologically relevant medium containing the cationic surfactant, cetrimide, was also investigated. All the media studied were capable of differentiating between the formulations employed, with formulation A consistently ranking high and formulations C and D ranking low. An in vivo dog study was carried out and an attempt was made to obtain a level A correlation between the plasma absorption curves and in vitro dissolution curves, using non-linear regression software. The in vitro-in vivo correlation (IVIVC) models developed indicated that fed state media (BDM 3) containing high levels of both bile salts (BS) and lipolysis products (LP) were best able to predict in vivo pharmacokinetic parameters (Cmax and AUC) with prediction errors lower than 10%. Overall, design and use of appropriate media for in vitro dissolution is extremely important. This study demonstrates the potential of physiologically relevant media containing both BS and LP for use in formulation and early drug development.     

Concentration profile for the dissolution of drug tablets undergoing simultaneous degradation

An empirical approach to the concentration-time history of a dissolving drug has resulted in a cube-root equation in which the characteristic constant of the equation embodies the important physical variables of the system. This expression has been used to study the dissolution of a drug that degrades simultaneously in the test solution. An alternative representation of the dissolution process is first-order kinetics. These two approaches are compared by fitting the experimental data of the dissolution of digoxin and melphalan tablets in various media, and a new method for the proper analysis of data for the dissolution of tablets that simultaneously degrade in the test solution is presented.This work was supported by Grant CA-17094 from the National Cancer Institute, and a donation by Burroughs Wellcome Company, Research Triangle Park, North Carolina.     

Statistical assessment of dissolution and drug release profile similarity using a model-dependent approach

A general multivariate procedure for assessing the similarity of dissolution and drug release profiles was developed. A mathematical model is fit to the data, and Hotelling's T(2) test is used to calculate the joint confidence region around the vector of differences between least-squares estimates of the parameters in the model. The method of Lagrange multipliers is used to determine if this confidence region is enclosed within a predetermined similarity region, and profile similarity is claimed if this is the case. The first-order, Gompertz, logistic, second-order, and Weibull models were fit to the in vitro extended-release profile of pseudoephedrine HCl from an asymmetric membrane (AM) film-coated osmotic tablet. The first-order model was selected because of its simplicity and because it was the best-fitting model according to a modified form of Akaike's Information Criterion. A nonlinear response surface model was also developed so that the formulator could calculate how much of the AM film coat should be applied in order to obtain the desired drug release profile. The usefulness of this model-dependent procedure was further demonstrated during an analytical method transfer exercise, where it was used to compare the drug release profiles obtained by two independent laboratories; additional research is required, however, before the appropriate acceptance criteria for demonstrating profile similarity can be recommended.     

A nonlinear mixed effects IVIVC model for multi-release drug delivery systems

The purpose of this analysis was the development of an IVIVC model, which involves a convolution step as described by O'Hara et al. and to describe a dual-release system: a controlled release formulation, which contains an initial immediate release element. Four formulations of Galantamine((R)) were used to test this modelling technique and a level A IVIVC, which meets the FDA criteria for internal and external validation, was successfully developed.     

IVIVC in oral absorption for fenofibrate immediate release tablets using a dissolution/permeation system

The usefulness of a dissolution/permeation (D/P) system to predict the in vivo performance of solid dosage forms containing the poorly soluble drug, fenofibrate, was studied. Biorelevant dissolution media simulating the fasted and fed state conditions of the human gastrointestinal tract were used in order to simulate the effect of food on the absorption of fenofibrate. Moreover, the results obtained from the D/P system were correlated with pharmacokinetic parameters obtained following in vivo studies in rats. The in vitro parameter (amount permeated in the D/P system) reflected well the in vivo performance in rats in terms of AUC and C(max) of fenofibric acid. This study thus demonstrates the potential of the D/P system as valuable tool for absorption screening of dosage forms for poorly soluble drugs.     

Nanocomposite formation between alpha-glucosyl stevia and surfactant improves the dissolution profile of poorly water-soluble drug

The formation of a hybrid-nanocomposite using α-glucosyl stevia (Stevia-G) and surfactant was explored to improve the dissolution of flurbiprofen (FP). As reported previously, the dissolution amount of FP was enhanced in the presence of Stevia-G, induced by the formation of an FP and Stevia-G-associated nanostructure. When a small amount of sodium dodecyl sulfate (SDS) was present with Stevia-G, the amount of dissolved FP was extremely enhanced. This dissolution-enhancement effect was also observed with the cationic surfactant of dodecyl trimethyl ammonium bromide, but not with the non-ionic surfactant of n-octyl-β-D-maltopyranoside. To investigate the dissolution-enhancement effect of Stevia-G/SDS mixture, the pyrene I(1)/I(3) ratio was plotted versus the Stevia-G concentration. The pyrene I(1)/I(3) ratio of Stevia-G/SDS mixture had a sigmoidal curve at lower Stevia-G concentrations compared to the Stevia-G solution alone. These results indicate that the Stevia-G/SDS mixture provides a hydrophobic core around pyrene molecules at lower Stevia-G concentrations, leading to nanocomposite formation between Stevia-G and SDS. The nanocomposite of Stevia-G/SDS showed no cytotoxicity to Caco-2 cells at a mixture of 0.1% SDS and 1% Stevia-G solution, whereas 0.1% SDS solution showed high toxicity. These results suggest that the nanocomposite formation of Stevia-G/SDS may be useful way to enhance the dissolution of poorly water-soluble drugs without special treatment.     

Search for technological reasons to develop a capsule or a tablet formulation with respect to wettability and dissolution

Proquazone, a poorly wettable compound, was used as a model drug in the search for reasons to develop a capsule or tablet formulation. The capsules were filled with proquazone as active ingredient, with lactose monohydrate (200 mesh) as filler and with magnesium stearate as lubricant. The tablet was made out of a granulate as internal phase which consisted of proquazone as active ingredient, lactose as filler, corn starch as disintegrant and PVP as a binding agent. The external phase consisted of magnesium stearate and corn starch. The concentration of proquazone in the capsule and in the tablet formulation was varied. The capsule formulations showed a significantly slower dissolution of the drug substance than the tablet formulations especially for a high-drug load. Independently of the drug load, only the tablet formulation showed a high-dissolution rate. Thus, concerning drug load, only the tablet formulations showed to be robust. It became clear that proquazone needs to be formulated as a granulate or a tablet to achieve a fast dissolution rate. Thus, a poorly wettable drug, especially when it is found in high concentrations, can have direct impact on the decision to develop a tablet or a capsule formulation.     

A review of methods used to compare dissolution profile data

In a number of recent guidance documents, the FDA has placed more emphasis on the meaningful comparison of dissolution profile data. For example, the FDA scale-up and post-approval changes–modified release (SUPAC–MR) guidance indicates that similar dissolution profiles for approved and modified formulations is acceptable justification for certain levels of change without prior FDA approval or the need to perform bioequivalence studies. As a result, interest among pharmaceutical scientists has focused on the methodology that is available for the comparison of dissolution profile data. The authors review the literature on the methods that are currently available.     

Mathematical modeling of drug dissolution

The dissolution of a drug administered in the solid state is a pre-requisite for efficient subsequent transport within the human body. This is because only dissolved drug molecules/ions/atoms are able to diffuse, e.g. through living tissue. Thus, generally major barriers, including the mucosa of the gastro intestinal tract, can only be crossed after dissolution. Consequently, the process of dissolution is of fundamental importance for the bioavailability and, hence, therapeutic efficacy of various pharmaco-treatments. Poor aqueous solubility and/or very low dissolution rates potentially lead to insufficient availability at the site of action and, hence, failure of the treatment in vivo, despite a potentially ideal chemical structure of the drug to interact with its target site. Different physical phenomena are involved in the process of drug dissolution in an aqueous body fluid, namely the wetting of the particle's surface, breakdown of solid state bonds, solvation, diffusion through the liquid unstirred boundary layer surrounding the particle as well as convection in the surrounding bulk fluid. Appropriate mathematical equations can be used to quantify these mass transport steps, and more or less complex theories can be developed to describe the resulting drug dissolution kinetics. This article gives an overview on the current state of the art of modeling drug dissolution and points out the assumptions the different theories are based on. Various practical examples are given in order to illustrate the benefits of such models. This review is not restricted to mathematical theories considering drugs exhibiting poor aqueous solubility and/or low dissolution rates, but also addresses models quantifying drug release from controlled release dosage forms, in which the process of drug dissolution plays a major role.     

药品经营企业开展药品不良反应监测工作的思考

通过对药品经营企业不良反应监测工作现状的描述,进一步分析、探讨药品不良反应工作的必要性与重要性,为今后如何开展药品不良反应监测工作提出了建议。     

Interpretation and optimization of the dissolution specifications for a modified release product with an in vivo-in vitro correlation (IVIVC)

This article considers the in vivo significance attached to in vitro dissolution testing. Almost invariably, the in vitro dissolution test is interpreted in terms of bioequivalence. The literature that describes methods for setting in vitro dissolution specifications is reviewed. The most common interpretation of these specifications is a deterministic one, that is, those batches passing the dissolution specifications would be bioequivalent with the reference if tested in vivo and those failing the dissolution specifications would not be bioequivalent if tested in vivo. Due to random variation, the deterministic interpretation is not appropriate. Instead, we need to consider the conditional probability that a batch that has passed the in vitro dissolution test would demonstrate bioequivalence if tested in vivo, and that a batch known to have failed the in vitro dissolution test would demonstrate bioinequivalence if tested in vivo. One way to estimate these probabilities is by means of a simulated experiment in which the production and testing (in vivo and in vitro) of a large number of batches is computer simulated. Such a simulation can only be performed if the relationship between the in vitro dissolution characteristics and the in vivo performance of the product has been modeled. These models are generally referred to as in vivo-in vitro correlations (IVIVC). The results of one such experiment are described. The above-mentioned conditional probabilities are shown to depend on the choice of dissolution specifications. This result leads to the notion of optimal dissolution specifications. However, both of the conditional probabilities cannot be maximized simultaneously. The probability of making a correct decision on the basis of the in vitro dissolution test is introduced as a possible optimality criterion. This probability is a linear combination of the two conditional probabilities of interest. Using this criterion, the optimal dissolution specifications can be found by searching over the multidimensional space defined by the half width of each interval used in the specifications to find the combination that maximizes this probability. This process is demonstrated using the Nelder-Mead search routine. The choice of dissolution specifications has profound implications for the routine production of the product because if the specifications were very narrow the probability of a batch passing would be low, resulting in a low hit rate. The same computer program used to perform the simulation experiment can be used to estimate the hit rate. Furthermore, it can be used to explore the magnitude of changes required in the parameters describing the test product (particularly variability) to increase a low hit rate to an acceptable level.     

Importance of dissolution profile in stability tests

The aim of stability testing lies in its possibility of revealing all the effects that may influence the quality, efficacy and safety of a pharmaceutical preparation. The stability of a dosage form means that the release of the active ingredients remains unchanged or within specific limits. The manner of stability testing is regulated by guidelines, which consist of -- besides the regular tests of the active ingredient and the degradation products, the concerning impurities, the water content, the hardness -- the dissolution tests. Most physical changes influence the drug release in vivo, which can -- in vitro -- be followed by dissolution.     

Integrating heterogeneous data to facilitate COVID-19 drug repurposing

In the COVID-19 pandemic, drug repositioning has presented itself as an alternative to the time-consuming process of generating new drugs. This review describes a drug repurposing process that is based on a new data-driven approach: we put forward five information paths that associate COVID-19-related genes and COVID-19 symptoms with drugs that directly target these gene products, that target the symptoms or that treat diseases that are symptomatically or genetically similar to COVID-19. The intersection of the five information paths results in a list of 13 drugs that we suggest as potential candidates against COVID-19. In addition, we have found information in published studies and in clinical trials that support the therapeutic potential of the drugs in our final list.     

Optimisation of culture conditions to develop an in vitro pulmonary permeability model.

An in vitro model to study pulmonary translocation was created, using the human cell line Calu-3 and primary rat type II pneumocytes. Cells were seeded on permeable membranes with a 0.4 microm or 3 microm pore size, utilizing different culture conditions such as medium formulation and cell density. The integrity of the cell monolayer was verified by measuring the transepithelial electrical resistance (TEER) and passage of sodium fluorescein. When seeded on inserts with 0.4 microm pore size, the Calu-3 cells and primary rat type II pneumocytes created high TEER values of 949+/-182 Omega cm(2) and 400+/-257 Omega cm(2), respectively. On membranes with 3 microm pores, Calu-3 cells achieved a high TEER value of 500+/-95 Omega cm(2). Our experiments indicate that the culture medium was more critical than the cell density, regarding the influence on TEER values. For both cell types a reduction of serum in the medium resulted in a decrease in TEER value. We established a good ('tight') monolayer of primary type II pneumocytes in Waymouth medium at a cell density of 0.9x10(6) cells/cm(2); the Calu-3 cells should be grown in DMEM medium containing Hepes at 0.75x10(6) cells/cm(2).     

Integrating pharmacogenomics into drug development

The first observations of inherited differences in drug effects in the 1950s led to the recognition of a genetic basis for drug response. With the development of genetics and molecular biology, it became clear that certain drug responses could be associated with specific genetic variations or polymorphisms. There are now examples of polymorphisms that affect response to drugs ranging from common analgesics to chemotherapeutics. The goal of pharmacogenetics is to identify polymorphisms that can serve as predictive markers of drug response. This review summarizes how existing pharmacogenomic technologies can be applied advantageously throughout drug development to bring drugs successfully to market along with diagnostic tests that ensure their appropriate use.     

药物溶出度测定仪的研究进展

药物溶出度试验是评价制剂品质和工艺水平的有效手段,也是检测固体制剂活性成分生物利用度和均匀度的一种有效方法．而所用的药物溶出度测定仪则是药典规定的检测固体药物制剂在规定的溶剂中溶出的速度和程度的专用仪器,因此,药物溶出度测定仪在评价药物溶出度时起着重要作用。本文就目前溶出度测定仪的优缺点进行总结,并对未来智能化药物溶出度测定仪的研制提出了新思路。     

Microenvironmental pH control of drug dissolution

Microenvironmental pH control has been used to modify the dissolution of pharmaceutical formulations in a predictive manner. An internal buffer system comprising disodium hydrogen orthophosphate and citric acid was incorporated at the 10% w/w level into a frusemide-polyvinylpyrrolidone (PVP) solid dispersion system which was X-ray amorphous, or non-crystalline, in nature. The dissolution rate, determined from constant surface area discs, was shown to be dependent on the phosphate/citric acid ratio of the internal buffer system. The approach proved successful for increasing the dissolution rate of a weakly acidic model drug in acidic media and retarding the dissolution rate in alkaline media. In an attempt to measure the pH at the “surface” of a dissolving compact a technique was developed that utilised a modified dissolution apparatus and a micro-pH probe. The data confirmed that the internal buffer system produced controlled changes in the measured surface pH. The surface pH-dissolution profiles for a series of internally buffered solid dispersions in two dissolution media (0.01 M sodium acetate and 0.01 M acetic acid) displayed a similar pattern to the pH-dissolution profile of an unbuffered X-ray amorphous frusemide-PVP solid dispersion in buffered dissolution media. This approach is proposed to be a useful method for producing controlled changes in the dissolution behaviour of pharmaceutical formulations and may be also applied to the prevention of crystallisation of drugs at the solid/liquid interface.