Raman-based real-time dissolution prediction using a deterministic permeation model.

The purpose of this study was to develop a deterministic permeation model (DPM) that predicts the in vitro release profile of an active ingredient (API) embedded in hydroxypropyl-methylcellulose (HPMC) matrix tablets based on Raman spectra. So far in the literature, such mechanistic models were utilized only for formulation optimization (off-line dissolution prediction), while the real-time prediction of dissolution profiles based on Process Analytical Technology (PAT) data was performed by empirical methods such as Partial Least Squares (PLS) regression. Our work represents a novel conceptual approach that utilizes a mechanistic model to predict dissolution profiles based on data yielded by PAT tools. Tablets containing various API- and HPMC-amounts were produced using different compression pressures according to a 33 full factorial design, their Raman spectra were recorded before dissolution testing. The DPM was constructed using one-third of the measured dissolution profiles and is presented as a system of differential equations together with its analytical solution. The parameters of DPM were estimated by the training data set containing the spectroscopically determined API- and HPMC- amounts and the tableting pressures used, then the release profiles of the remaining two-thirds of the tablets were predicted. The Raman spectra-based predictions of DPM were compared with predictions of an Artificial Neural Network (ANN). It was found that the two methods yield similar results, however, the mechanistic approach has the benefit of requiring a lower amount of training samples. Although the model is based on a remarkable simplification of reality, it facilitates a deeper understanding of the behavior of the formulation. The DPM could improve our understanding of the effect of HPMC and tableting pressures on the release kinetics of the HPMC matrix tablets and participate in the development of PAT-based new surrogate dissolution methods for Real-Time Release testing (RTRt).

Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration.

Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxy-clarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The pharmacokinetics of clarithromycin and its 14(R)-hydroxyl metabolite were adequately described by a one-compartment model each for clarithromycin and its metabolite as well as an inhibition compartment that reflects the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.

Comparison of dissolution time profiles: No similarity but where is the difference?

The similarity of the dissolution time profiles is routinely determined by various statistical methods, e.g. by calculating the f2 similarity factor, by calculating the multivariate statistical distance or determining the confidence interval of f2 metrics using the bootstrapping method. If the similarity of the dissolution profiles is not achieved, these methods provide no information about the possible causes of the differences in the final dosage forms. In this article it is shown that after introduction of summary parameters into the disintegration-dissolution model (DDM), such as intrinsic lifetime distribution of particles, saturation state function, drug load of the system and applying population data analysis, differences on the level of intrinsic lifetime distributions of particles of active pharmaceutical ingredient in immediately release formulations are identified. The identification of these differences provides important clues to target development of generic formulations or helps to explain possible differences in the in vivo behavior of products.

Physicochemical pharmacokinetics as an optimization tool for generic development: A case study.

In spite of the fact that dissolution time profiles of 250mg ursodeoxycholic acid (UCDA) capsules developed by Sponsor and 250mg hard capsules produced by Ursofalk®, Dr. Falk Pharma GmbH, indicated similarity (f2=60.6), a bioavailability study indicated unexpected differences in the formulations. To find an explanation of the in vivo performance of the compared formulations, the dissolution profiles were analyzed using a novel dissolution theory considering: The dissolution model was applied to the measured data using SADAPT. Despite Cmax and AUC values showing higher values after administration of the test product, a reduction of UDCA particle size for the test formulation was suggested for reformulation. The decision was based on the strongly pH-dependent UDCA solubility, formation of insoluble crystals at low pH condition and the known high pH fluctuations ranging from pH1 to 8 in empty stomach. The performed reformulation led to increased dissolution rate of the test product and to a positive bioequivalence study which compared the reformulated test generic formulation with two reference products purchased from two highly regulated markets.

Asymptotics and bioavailability in a 17-compartment pharmacokinetic model with enterohepatic circulation and remetabolization.

A 17-compartment linear pharmacokinetic model is designed, describing the complex process of enterohepatic circulation as a superposition of the net (remetabolizationfree) enterohepatic circulation, and remetabolization with subsequent intestinal absorption of the parent drug. Basically, the model is built by doubling the model describing the circulation of the parent drug in the body, so that the remetabolizable metabolite circulates in a model of the same structure as does the parent compound. The two submodels are cross-connected with arrows denoting the transition of the particular substance into the complementary part of the complex model. Asymptotic properties of the model are investigated, in particular, explicit formulas for its pharmacokinetic endpoints are given using the elements of its transition probability matrix. Conversely, taking account of the effect of bile cannulation, intravenous, intraportal and oral administration of the drug, as well as of the intravenous and intraportal administration of the remetabolizable metabolite, the transition probabilities of the system are determined in terms of certain measurable pharmacokinetic endpoints and the flow rates through the kidneys, liver and the cardiac output. Finally, the influence of the enterohepatic circulation and remetabolization process on bioavailability is examined. In particular, the inclusion-exclusion formula is derived, expressing its joint efficiency (defined as the relative increase of bioavailability) by means of the efficiencies of the net enterohepatic circulation and of the remetabolization process.

Dissolution and coarsening of polydisperse, polymorph drug particles liberated from a disintegrating finished dosage form: Theoretical considerations.

In order to improve the bioavailability of substances with limited water-solubility, they are often formulated as nanoparticles. Nanoparticles show enhanced dissolution properties when compared to large particles. In this paper a dissolution theory is presented that comprehensively describes the dissolution properties of both large- and nanoparticles. It comprises non-sink conditions and arbitrary shaped isometrically dissolving particles, considering particle-size-independent dissolution layer thickness and several polymorphic drug forms. The known root-laws of dissolution kinetics happen to be special cases that depend on particle-size in relation to the diffusion layer thickness i.e. whether the particles are much larger, comparable, or much smaller than the diffusion layer thickness. The presented theory explains the improved dissolution properties of nanoparticles, such as their increased solubility, almost immediate dissolution, and the dissolution kinetics which is independent from hydrodynamic conditions. For polydisperse, polymorphic particles of arbitrary shapes that are liberated from a disintegrating finished dosage form, the Ostwald ripening (coarsening of particles and transition of metastable polymorphic forms into a more stable crystalline form) is described as water mediated mass transport. The presented theory points to certain limitations of the Ostwald-Freundlich equation for nanoparticles and provides their better characterization. This way it may contribute to a more specifically targeted development of finished dosage forms and may help to reduce the bias of toxicological and environmental assessments especially for drugs that are formed as nanoparticles.

Population data analysis of dissolution time profiles: Assessment of physicochemical properties of the drug, drug particles and the pharmaceutical formulation.

Disintegration of finished dosage forms (FDF) and drug dissolution are fundamentally important processes that affect bioavailability. Established theories do not account for disintegration and usually assume sink conditions for drug dissolution that often do not apply. We present the theory to describe the disintegration of FDF with subsequent dissolution of liberated particles containing the active pharmaceutical ingredient (API) and its application using population data analysis. Population modeling, using dissolution profiles of 400mg cefditoren pivoxil tablets manufactured under various tableting pressures, characterized the intrinsic lifetime distribution of the particles and identified the presence of crystalline API in the formulation that was proven by X-ray diffraction. Modeling further estimated the disintegration time of FDF, the solubility of the amorphous API and its chemical instability in the medium that were in agreement with the experimentally determined values. This novel approach provides a quantitative understanding of the manufacturing process of FDF and can substantially contribute to the targeted development of finished dosage forms.

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans.

Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3-3 mg/kg; oral doses, 1-10 mg/kg), 34 dogs (intravenous doses, 0.3-1 mg/kg; oral doses, 1-10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20-480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9-88.7%) in rats, 33.3% (24.0-45.9%) in dogs, and 65.6% (56.5-72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85-8.85) as high in rats, 1.50-fold (1.32-1.85) in dogs, and 2.91-fold (2.30-3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0-59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1-43.9%) under fasting and 18.2% (12.2-31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng·h/mL for 60 mg fimasartan compared with 424 ± 63 ng·h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.

Asymptotics and bioavailability in multicompartment pharmacokinetic models with enterohepatic circulation.

Analysing discrete as well as continuous linear autonomous pharmacokinetic models, it is shown that their asymptotic behaviour is independent of the rates of kinetic processes and timing of drug application. Consequently, for the description of pharmacokinetic endpoints, i.e. the total amounts of drug eliminated through different organs under various ways of administration, in such a model the knowledge of total amounts delivered to individual compartments and its transition probability matrix P=[p(ij)] is sufficient.A design and analysis of a 9-compartment pharmacokinetic model with enterohepatic circulation (EHC), avoiding several common simplifications, test the applicability of our method. The central compartment of the model is the liver acting as filter and linking the systemic and enterohepatic circulation. Explicit formulas are given for pharmacokinetic endpoints of the model using the elements of the transition probability matrix P. Conversely, the transition probabilities are determined in terms of certain measurable pharmacokinetic endpoints and the flow rates through the kidneys, liver and the cardiac output, contributing that way to the structural identifiability problem. As a further consequence, the bioavailability of the drug with and without EHC can be determined and the efficiency of EHC expressed as the 'probability' of the enterohepatic cycle.Finally, we apply our method to analyse and compare various pharmacokinetic models, describing the EHC of drugs, based on some previously published articles.

Differences between lovastatin and simvastatin hydrolysis in healthy male and female volunteers:gut hydrolysis of lovastatin is twice that of simvastatin.

The aim of this pharmacokinetic evaluation was to show the effect of the extra methyl group in simvastatin on esterase hydrolysis between lovastatin and simvastatin in male and female volunteers. This study was based on the plasma concentration-time curves and the pharmacokinetics of lovastatin and simvastatin with its respective active metabolite statin-beta-hydroxy acid obtained from two different bioequivalence studies, each with 18 females and 18 males. Results were: The group of female volunteers showed a higher yield of the active metabolite beta-hydroxy acid than the group of males (p < 0.002) for both lovastatin and simvastatin. This difference was not related to the body weight of both groups. In the male/female groups, subject-dependent yield of active metabolite beta-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of data points when the AUCt lovastatin was plotted vs. that of the beta-hydroxy acid metabolite. In the fan of data points, subgroups could be distinguished, each showing a different regression line and with a different Y-intercept (AUCtbeta-hydroxy acid). Lovastatin hydrolysis was higher than simvastatin hydrolysis. It was possible to discriminate between hydrolysis of both lovastatin and simvastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing different but high yield of statin beta-hydroxy acid can be explained by variable hydrolysis of plasma and hepatic microsomal and cytosolic carboxyesterase activity. This study showed clearly that despite the subject-dependent hydrolysis of lovastatin/simvastatin to the active metabolite, males tend to hydrolyse less than females. The extra methyl group in simvastatin results in less hydrolysis due to steric hindrance.

Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose.

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 x 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = microg x h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation. There is a large variation in the ramiprilat t1/2beta (50-60% CV). There is a group of subjects who showed a t1/2beta of approximately 80 h (15% CV), and two apparent groups with a longer t1/2beta for each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean +/- SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females. This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

Lack of Male-Female Differences in Disposition and Esterase Hydrolysis of Ramipril to Ramiprilat in Healthy Volunteers after a Single Oral Dose.

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 × 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = mg.h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation.There is a large variation in the ramiprilat t1/2ß (50-60% CV). There is a group of subjects who showed a t1/2ß of approximately 80 h (15% CV), and two apparent groups with a longer t1/2ßfor each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean ± SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt /kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females.This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

Disintegration rate and properties of active pharmaceutical ingredient particles as determined from the dissolution time profile of a pharmaceutical formulation: an inverse problem.

Dissolution profile of a finished dosage form (FDF) contains hidden information regarding the disintegration of the form and the particle properties of the active pharmaceutical ingredient. Here, an extraction of this information from the dissolution profile without limitation to sink conditions is provided. In the article, mathematical relationships between the continuously measured dissolution profile of an FDF containing uniform or heterogeneous particles and its disintegration rate are developed. Further, the determinability of the disintegration kinetics and particle properties released from an FDF using the derived recurrent procedure was analyzed. On the basis of the theoretical data sets, it was demonstrated that the introduced analysis of dissolution profiles correctly identifies the disintegration rate of FDF containing multiple particle types. Furthermore, for known disintegration rates, the intrinsic lifetime of particles (time needed for total particle dissolution in infinite volume) released from the FDF and their relative amount can be determined. The extractable information from FDF dissolution time profiles can be utilized in designing of the formulation process, resulting in improved understanding of FDF properties, contributing thus to the implementation of quality by design in the FDF development.

Characterization of an active pharmaceutical ingredient by its dissolution properties: amoxicillin trihydrate as a model drug.

To characterize the dissolution of particles, a dissolution rate coefficient alpha, consisting of a geometric factor gamma and material constant mu, was introduced. The impact of the particle geometry on the initial rate of dissolution was assessed for spherical, cubic and tetrahedral particles. Additionally, a description of dissolution of samples containing multiple populations of particles was derived. A two-population model was employed to characterize sieved fractions of amoxicillin trihydrate. The investigation, using factor analysis, of the influence of dose, particle size and agitation intensity on the dissolution rate coefficient alpha indicated the presence of disintegrating agglomerates in larger particles. Based on the dissolution characteristics of particular particle size fractions and on the determined particle size distribution, the dissolution profile of the mixed sample containing nine sieved fractions in size was successfully predicted. Finally, the limitations of the film theory are discussed in light of the multiple-population dissolution theory.