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1.
Mol Pharm ; 21(7): 3540-3552, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38900044

RESUMEN

Molecular dynamics (MD) simulations of linear amylose fragments containing 10 to 40 glucose units were used to study the complexation of the prototypical compound, 3-pentadecylphenol (PDP)─a natural product with surfactant-like properties─in aqueous solution. The amylose-PDP binding leverages mainly hydrophobic interactions together with excluded volume effects. It was found that while the most stable complexes contained PDP inside the helical structure of the amylose in the expected guest-host (inclusion) complexation manner, at higher temperatures, the commonly observed PDP-amylose complexes often involved more nonspecific interactions than inclusion complexation. In the case where a stoichiometric excess of PDP was added to the simulation box, self-aggregation of the small molecule precluded its ability to enter the internal helical part of the oligosaccharide, and as a result, inclusion complexation became ineffective. MD simulation trajectories were analyzed preliminarily using cluster analysis (CA), followed by more rigorous solvent accessible surface area (SASA) determination over the temperature range spanning from 277 to 433 K. It was found that using the SASA of PDP corrected for its intrinsic conformational changes, together with a generic hidden Markov model (HMM), an adequate quantification of the different types of PDP-amylose aggregates was obtained to allow further analysis. The enthalpy change associated with the guest-host binding equilibrium constant (Kgh) in aqueous solution was estimated to be -75 kJ/mol, which is about twice as high as one might expect based on experimentally measured values of similar complexes in the solid state where the (unsolvated) helical structure of amylose remains rigid. On the other hand, the nonspecific binding (Kns) enthalpy change associated with PDP-amylose interactions in the same solution environment was found to be about half of the inclusion complexation value.


Asunto(s)
Amilosa , Simulación de Dinámica Molecular , Fenoles , Amilosa/química , Fenoles/química , Agua/química , Interacciones Hidrofóbicas e Hidrofílicas , Tensoactivos/química , Temperatura , Termodinámica
2.
Mol Pharm ; 20(10): 5135-5147, 2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37671526

RESUMEN

Aggregation in aqueous solution can have important implications on both the in vivo exposure of a drug and its pharmaceutical manufacturability. However, the drug aggregates formed can be very small and, thus, difficult to interrogate experimentally. On the other hand, at higher supersaturations where larger aggregates are supported, the chemical system is inherently metastable and therefore likewise challenging to study from an experimental standpoint. Understanding aggregation behavior is further complicated in the case of ionizable drugs where, unlike neutral compounds, there can be uncertainty in the kinds of drug molecules (i.e., charged, neutral, or both) that become incorporated into various clusters, particularly at pH values near the pKa. In this paper, we apply physics-based all-atom molecular dynamics (MD) simulations to study aggregation in the weakly basic drug papaverine and in the weakly acidic drug prostaglandin F2α. We employ in silico tools to construct simulation workflows and comprehensive cluster analysis protocols to elucidate the size distributions and dynamics of the drug aggregates formed at both an experimentally relevant concentration and at high supersaturation. We build on a previously published treatment [Solubility of sparingly soluble ionizable drugs. Adv. Drug Deliv. Rev. 2007, 59, 568-590, DOI: 10.1016/j.addr.2007.05.008] to translate the predicted aggregate distributions of each ionized drug into corresponding pH-solubility curves that can be compared directly to experiment. Our findings show that the assumption of a single predominant (charged) aggregate can be misleading in interpreting experimental pH-solubility curves, as it does not adequately reflect the rich diversity revealed in our simulations. Beyond not accounting for the distribution of ionized drug-containing clusters actually observed in solution, for both drugs we find evidence that neutral drug molecules can also participate in the aggregation phenomena. Notably, we observe that many drug molecules remain as free monomers in solution even under simulated conditions designed to mimic those where there is significant deviation of the experimental pH-solubility curve from the Henderson-Hasselbalch (H-H) equation, often taken to be a clear signpost of drug aggregation.

3.
Mol Pharm ; 17(1): 219-228, 2020 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-31809062

RESUMEN

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a "kinetic solubility" effect), characterizing its duration (i.e., the so-called "parachute" effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial "denucleation" (dissolution) character. On the other hand, "nucleation and growth" (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution-recrystallization transient of the drug, obtaining a fit of R2 = 0.993. By precisely characterizing the duration of the "parachute" in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.


Asunto(s)
Preparaciones Farmacéuticas/química , Química Farmacéutica , Cristalización , Gliburida/química , Indometacina/química , Cinética , Loratadina/química , Modelos Químicos , Solubilidad , Terfenadina/química
4.
Analyst ; 145(3): 745-749, 2020 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-31844854

RESUMEN

Solid-state reactions and phase transformations in which the activation energy changes with the extent of conversion, e.g. multi-step or dispersive kinetic processes, cannot be reliably treated using current thermal methods, particularly when it comes to handling non-isothermal data sets. New models that consider distributed reactivity and/or the potential temperature-dependence of the pre-exponential term in the Arrhenius equation are urgently needed and, based on them, the extension of current theory to appropriately treat non-isothermal data. Numerical methods could prove useful in overcoming the variable-separability problem that can hinder the analytic solution of more complex kinetic relationships.

5.
AAPS PharmSciTech ; 20(1): 34, 2019 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-30603812

RESUMEN

Compared to more traditional top-down processing, the less common route to preparing drug nanocrystals through direct synthesis, e.g., starting with the nucleation of dissolved drug molecules (bottom-up processing), can offer both speed and cost advantages that makes it worthy of investigation. The current, theoretical work puts forth a technical basis and simulated results that could provide additional impetus for conducting further experimental work in this area. Specifically, an asymmetrical particle size distribution generated through the nucleation of a typical small-molecule drug, mirrored after carbamazepine hydrate based on a recent work [Skrdla PJ. J Phys Chem C 116:214-25, 2012], is subject to growth over time by a particle-coarsening mechanism using simulations of Ostwald ripening. Compared to a symmetrical, Gaussian distribution under the same conditions (fixed, relatively low concentration of free drug molecules in solution), it is found that, at longer times, the asymmetrical distribution formed through nucleation broadens more slowly. This finding could represent an additional benefit of synthetic strategies for the preparation of nano-formulations, previously unreported.


Asunto(s)
Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Nanopartículas/química , Tamaño de la Partícula , Estabilidad de Medicamentos
6.
Phys Chem Chem Phys ; 19(31): 20523-20532, 2017 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-28730199

RESUMEN

Predicting the glass transition temperature (Tg) of mixtures has applications that span across industries and scientific disciplines. By plotting experimentally determined Tg values as a function of the glass composition, one can usually apply the Gordon-Taylor (G-T) equation to determine the slope, k, which subsequently can be used in Tg predictions. Traditionally viewed as a phenomenological/empirical model, this work proposes a physical basis for the G-T equation. The proposed equations allow for the calculation of k directly and, hence, they determine/predict the Tg values of mixtures algebraically. Two derivations for k are provided, one for strong glass-formers and the other for fragile mixtures, with the modeled trehalose-water and naproxen-indomethacin systems serving as examples of each. Separately, a new equation is described for the first time that allows for the direct determination of the crossover temperature, Tx, for fragile glass-formers. Lastly, the so-called "Rule of 2/3", which is commonly used to estimate the Tg of a pure amorphous phase based solely on the fusion/melting temperature, Tf, of the corresponding crystalline phase, is shown to be underpinned by the heat capacity ratio of the two phases referenced to a common temperature, as evidenced by the calculations put forth for indomethacin and felodipine.

7.
Langmuir ; 28(10): 4842-57, 2012 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-22324463

RESUMEN

Kinetic models for nucleation, denucleation, Ostwald ripening (OR), and nanoparticle (NP) aggregation are presented and discussed from a physicochemical standpoint, in terms of their role in current NP preparations. Each of the four solid-state mechanisms discussed predict a distinct time dependence for the evolution of the mean particle radius over time. Additionally, they each predict visually different particle size distributions (PSDs) under limiting steady-state (time-independent) conditions. While nucleation and denucleation represent phase transformation mechanisms, OR and NP aggregation do not. Thus, when modeling solid-state kinetics relevant to NP processing, either the time evolution of the mean particle radius or the fractional conversion data should be fit using appropriate models (discussed herein), without confusing/combining the two classes of models. Experimental data taken from the recent literature are used to demonstrate the usefulness of the models in real-world applications. Specifically, the following examples are discussed: the preparation of bismuth NPs, the synthesis of copper indium sulfide nanocrystals, and the aggregation of neurological proteins. Because the last process is found to obey reaction-limited colloid aggregation (RLCA) kinetics, potential connections between protein aggregation rates, the onset of neurological disease, and population lifespan dynamics are suggested by drawing a parallel between RLCA kinetics and Gompertz kinetics. The physical chemistry underpinning NP aggregation is investigated, and a detailed definition of the rate constant of aggregation, k(a), is put forth that provides insight into the origin of the activation energy barrier of aggregation. For the two nanocrystal preparations investigated, the initial kinetics are found to be well-described by the author's dispersive kinetic model for nucleation-and-growth, while the late-stage NP size evolution is dominated by OR. At intermediate times, it is thought that the two mechanisms both contribute to the NP growth, resulting in PSD focusing as discussed in a previous work [Skrdla, P. J. J. Phys. Chem. C2012, 116, 214-225]. On the basis of these two mechanisms, a synthetic procedure for obtaining monodisperse NP PSDs, of small and/or systematically targeted mean sizes, is proposed.


Asunto(s)
Nanopartículas/química , Enfermedades del Sistema Nervioso/etiología , Envejecimiento/metabolismo , Animales , Fenómenos Biofísicos , Bismuto/química , Humanos , Cinética , Sustancias Macromoleculares/química , Conceptos Matemáticos , Nanopartículas del Metal/química , Modelos Moleculares , Modelos Neurológicos , Complejos Multiproteicos/química , Neoplasias/etiología , Neoplasias/metabolismo , Proteínas del Tejido Nervioso/química , Enfermedades del Sistema Nervioso/metabolismo , Tamaño de la Partícula , Multimerización de Proteína , Termodinámica
8.
J Phys Chem A ; 115(24): 6413-25, 2011 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-21595487

RESUMEN

The activation energy distributions underpinning the two complementary dispersive kinetic models described by the author in a recent work (Skrdla, P. J. J. Phys. Chem. A 2009, 113, 9329) are derived and investigated. In the case of nucleation rate-limited conversions, which exhibit "acceleratory" sigmoidal transients (a kind of S-shaped stretched exponential conversion profile), an activation energy distribution visually similar to the Maxwell-Boltzmann (M-B) distribution is recovered, consistent with the original derivation of that model. In the case of predominantly "deceleratory" conversions, the activation energy distribution is skewed from normal in the opposite direction. While the "M-B-like" activation energy distribution supports the empirical observation of a rate enhancement as a function of the conversion time in nucleation rate-limited processes, the complementary distribution, with its pronounced low-energy tail, reflects a slow-down in the specific rate as the conversion progresses, consistent with experimentally observed denucleation rate-limited conversions. Activation energy distributions were also plotted for real-world data (Qu, H.; Louhi-Kultanen, M.; Kallas, J. Cryst. Growth Des. 2007, 7, 724), depicting the impact of various additives on the nucleation rate-limited kinetics of the solvent-mediated phase transformation of the crystalline drug carbamazepine. Last, by coupling the author's dispersive kinetic description of the time-dependent activation energy for nucleation to the classical description of the critical nucleus energy provided by the Kelvin equation, an accelerated hopping mechanism for the diffusion of monomers to the growing embryo surface was observed. That hopping mechanism was rationalized by modifying the Einstein-Smoluchowski (E-S) equation to allow it to describe the "supra-brownian" molecular motion thought to lie at the heart of nucleation kinetics.

9.
Int J Pharm ; 595: 120228, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33484924

RESUMEN

Salt formation can enable the development of poorly water-soluble drugs containing at least one ionizable moiety. Not only can salts offer a solubility enhancement that can sometimes far exceed that of other commonly used solubilization strategies applied across the pharmaceutical industry, they can simultaneously bestow additional benefits such as providing low-cost formulation options. The goal of this work is to put forth a simple methodology to enable one to accurately predict the maximal solubility advantage of acidic and basic drugs whose unionized conjugate (neutral parent molecule) is poorly soluble. While published equations leveraging the Henderson-Hasselbalch/H-H relationship reasonably estimate the thermodynamic solubility limit (in systems where there is no supersaturation), under physiologically relevant conditions the maximal/kinetic solubility can play an important role in determining oral bioavailability, as in the case of amorphous drugs. Under these circumstances, a higher solubility can be maintained for short durations through drug supersaturation provided that the precipitation is slow, thereby causing deviations from H-H predictions. It is possible also that, in some instances, supersaturation could coincide with behavior previously attributed to drug aggregation in solution. The proposed methodology utilizes speciation across the pH range to allow one to determine the maximal amount of ionized and unionized drug in solution at each pH. The calculation is easily extended to cases where the counterion serves as a competing weak acid, weak base, or as a common ion. Additionally, a more thorough assessment of the Gibbs free energy change associated with the solubilization of salts is also presented, as this energy describes the key driving force for the recrystallization of the neutral parent by triggering its nucleation. Lastly, to demonstrate applicability to real-world compounds containing multiple ionizable moieties, the complex pH-solubility profile of a drug maleate salt taken from the literature is simulated.


Asunto(s)
Preparaciones Farmacéuticas/química , Sales (Química)/química , Administración Oral , Disponibilidad Biológica , Química Farmacéutica , Simulación por Computador , Cristalización , Concentración de Iones de Hidrógeno , Cinética , Modelos Químicos , Soluciones Farmacéuticas/química , Farmacocinética , Solubilidad , Termodinámica
10.
Phys Chem Chem Phys ; 12(15): 3788-98, 2010 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-20358035

RESUMEN

Oscillatory kinetic behavior is reported for the first time in a solid-state phase transformation of an organic compound, specifically, in the dissolution of Form V crystals of etoricoxib in neat toluene. The dissolution involves kinetics of bistability due to the generation of a second polymorph, Form I, during the process. While an attempt is made to reconcile the periodic behavior with the oscillatory rate coefficient predicted by time-dependent Marcus theory, more successful simulations of the data are obtained using superimposed, elementary dispersive kinetic models for both dissolution and nucleation-and-growth. Contrastingly, the dissolution of Form V in toluene containing a suspected small quantity of methanol/base contaminant shows that the phase transformation of Form V to the less-stable Form I crystals is rate-limiting and that the process is well described by a single, elementary dispersive kinetic model (i.e., no oscillations are observed). The latter observation lends support to the bistability hypothesis and provides evidence for the existence of a 'corollary' to Ostwald's rule of stages.


Asunto(s)
Piridinas/química , Sulfonas/química , Cristalización , Etoricoxib , Cinética , Modelos Químicos , Modelos Moleculares , Factores de Tiempo , Tolueno/química
11.
Talanta ; 208: 120400, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31816711

RESUMEN

The profoundly fast flow rates, observed at unexpectedly low column back-pressures, of capillaries packed with colloidal silica-based stationary phases is explained using slip flow theory applied to the particles themselves rather than the capillary walls. An equation is proposed that leverages nanoscale thermodynamics, geometrical considerations and Hagen-Poiseuille flow without the traditional no-slip boundary condition. It is found that the proposed model successfully fits/predicts real-world data taken from the literature, presented in a plot of the observed flow (enhancement) as a function of the (diminishing) mean particle size, so long as the particles do not exceed ~1 µm. This finding lends support to the continued use of colloidal silica packings in liquid chromatographic applications to achieve efficient separations of molecules on the smallest scale.

12.
J Pharm Sci ; 109(4): 1627-1629, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31930977

RESUMEN

The solubility enhancement generated by an amorphous phase over its crystalline counterpart is unaffected by the pH of the solution (at fixed ionic strength and temperature), even for a drug containing ionizable moieties, provided that both the ionized and neutral species generated through dissolution of the solids remain dissolved.


Asunto(s)
Preparaciones Farmacéuticas , Cristalización , Concentración de Iones de Hidrógeno , Concentración Osmolar , Solubilidad
13.
J Phys Chem A ; 113(33): 9329-36, 2009 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-19719293

RESUMEN

The potential applications of dispersive kinetic models range from solid-state conversions to gas-phase chemical physics and to microbiology. Here, the derivation and application of two such models, for use in solid-state applications, is presented. The models are based on the concept of a Maxwell-Boltzmann distribution of activation energies. The ability of the models to fit/explain an assortment of asymmetric, sigmoidal conversion-versus-time transients presented in the recent literature, as well as to provide physicochemical interpretations of the kinetics via the two fit parameters, alpha and beta, makes them a powerful tool for understanding nucleation/denucleation rate-limited processes that are involved in many phase transformations, dissolutions and crystallizations.


Asunto(s)
Modelos Químicos , Transición de Fase , Cristalización , Ácido Glutámico/química , Cinética , Tamaño de la Partícula , Solventes/química , Teofilina/química , Tiazoles/química
14.
Int J Pharm ; 567: 118465, 2019 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-31279056

RESUMEN

The accurate prediction of the solubility enhancement offered by neat amorphous drugs and amorphous solid dispersions, over their crystalline (API) counterparts, has been discussed in several landmark works dating back at least two decades. Against this backdrop, an assessment of the current state-of-the-art for rigorously, yet simply (circumventing computational methods), determining the amorphous:crystalline solubility ratio based on thermo-analytical quantities is presented herein. Included in this work is a brief survey of the literature together with a discussion of the advantages and shortcomings of some of the most popular approaches, to-date. While the focus is on neat amorphous drugs, both before and after moisture sorption, the methodology presented is readily extended to more complex (e.g. ternary) systems that form a single, homogeneous phase. Six key questions are addressed in the context of how to most accurately determine the amorphous:crystalline solubility ratio: (1) How is the lattice energy of the crystalline phase assessed? (2) What is the role of heat capacity? (3) How does the pKa impact the solubility ratio prediction (for ionizable drugs)? (4) How does one incorporate the effects of moisture sorption on the amorphous phase? (5) How might one characterize (predict) the rate of drug recrystallization under various conditions (since the duration of the solubility enhancement is a kinetic phenomenon)? (6) What is the best approach for linking the (loss in) solubility enhancement to the Tg-lowering of the amorphous drug (by water) and vice-versa? In addressing these questions, this work aims to put forth a standardized methodology for determining the amorphous solubility enhancement with improved accuracy.


Asunto(s)
Modelos Teóricos , Química Farmacéutica , Cristalización , Cinética , Preparaciones Farmacéuticas/química , Solubilidad , Termodinámica
15.
Int J Pharm ; 555: 100-108, 2019 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-30448307

RESUMEN

Water is often readily absorbed by amorphous compounds, lowering their glass transition temperature (Tg) and facilitating their recrystallization (via nucleation-and-growth). At the same time, the increase in moisture content translates to a decrease in both the thermodynamic solubility and intrinsic dissolution rate, as compared to the corresponding dry (pure) amorphous phase, e.g. see [Murdande SB, Pikal MJ, Shanker RM, Bogner RH. 2010. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J Pharm Sci 99:1254-1264.]. In the case of pure indomethacin and felodipine, the solubility advantage of each amorphous phase over its crystalline counterpart were previously determined to be 7.6 and 4.7, respectively, using a new methodology together with basic calorimetric data taken from the literature. Herein, we demonstrate that, theoretically, following the uptake of just ∼0.5% w/w water, the solubility ratios decrease to 6.9 and 4.5, in the same order. Moreover, as the predicted intrinsic dissolution rate (based on the Noyes-Whitney equation) is directly proportional to the solubility advantage of a given amorphous-crystalline pair, it decreases proportionately upon moisture uptake. Applying the methodology presented herein, one can directly predict the extent of Tg-lowering observed at any moisture content, for a given amorphous phase. Knowing that value, it is possible to estimate the relative decrease in the solubility and/or intrinsic dissolution rate of the plasticized phase compared to the pure glass, and vice-versa.


Asunto(s)
Química Farmacéutica/métodos , Felodipino/administración & dosificación , Indometacina/administración & dosificación , Agua/química , Calorimetría/métodos , Cristalización , Liberación de Fármacos , Felodipino/química , Indometacina/química , Solubilidad , Termodinámica , Temperatura de Transición , Vitrificación
16.
J Pharm Biomed Anal ; 47(2): 312-9, 2008 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-18295428

RESUMEN

The solvolysis kinetics of a developmental active pharmaceutical ingredient (API) were investigated using a high temperature (HT)-HPLC reactor approach to determine whether it might be possible to use the technique to efficiently screen the relative stabilities of typical APIs (particularly those that are stable at the column temperatures achievable on most HPLC systems and over durations of less than 60 min-a reasonable upper limit for typical method run time). It was discovered that the on-column API degradation kinetics better obeyed a second-order model than a first-order one. Employing a newly developed mathematical treatment, the apparent activation energy for the process was determined to be 85.7+/-1.6 kJ/mol; the apparent frequency factor was found to be (3.9+/-0.4)x10(4) s(-1). The retention mechanism of the API on the C18-modified zirconia column (ZirChrom) Diamondbond-C18) was investigated using a van't Hoff analysis. It was discovered that the logarithm of the retention factor (following correction for the gradient elution of the assay method) exhibited a quadratic dependence on the reciprocal of the absolute temperature. While the retention was found to be predominantly enthalpically driven over the majority of temperatures investigated in this study (ranging from 40 to 200 degrees C), a regression fit of the curve predicted a maximum at approximately 20 degrees C, indicative of a transition from predominantly enthalpically controlled retention to a mainly entropically driven mechanism. A table summarizing the thermodynamic retention parameters at each experimental column temperature is provided. Finally, the preliminary application of the HT-HPLC reactor approach to the study of degradation kinetics of other APIs is discussed in terms of some unexpected findings obtained using the zirconia column.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Preparaciones Farmacéuticas/química , Solventes/química , Circonio/metabolismo , Estabilidad de Medicamentos , Cinética , Temperatura , Termodinámica , Circonio/química
17.
J Pharm Sci ; 96(8): 2107-10, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17301967

RESUMEN

The isothermal crystallization of glycine in a 40/60 (w/w) sucrose/glycine excipient system is examined with the goal of comparing the kinetic information obtained by using the Johnson-Mehl-Avrami (JMA) equation with that collected using a novel, dispersive kinetic model equation recently proposed by the author. It is found that while both models explain the experimental data reasonably well, the latter equation fits the data, collected at temperatures in the range 241-251 K, without the use of empirical parameters. The values of the activation energy and Arrhenius constant (frequency factor) for both models agree within experimental error.


Asunto(s)
Excipientes/farmacocinética , Glicina/farmacocinética , Sacarosa/farmacocinética , Cristalización , Excipientes/química , Liofilización , Glicina/química , Cinética , Modelos Teóricos , Sacarosa/química
18.
J Pharm Biomed Anal ; 45(2): 251-6, 2007 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-17662549

RESUMEN

A new semi-empirical model, particularly useful for studying complex dissolution kinetics, is presented here. It uses only two 'fit parameters', each possessing physically relevant units (in the time domain). The model is based on the idea that dispersion (variation) in the activation energy barrier may arise in certain cases, as a result of (quantized) molecular kinetic energies affecting the speed of the rate-determining step (r.d.s.) of the dissolution event. For such 'dispersive dissolutions', the r.d.s. is assumed to involve 2D denucleation. The author's dispersive kinetic model is shown to be applicable to the dissolution of various formulations of norfloxacin which produce very asymmetric, sigmoidal concentration versus time (C-t) profiles. It is derived by assuming an activation energy distribution having the functional form of the Maxwell-Boltzmann (M-B) distribution, coupled with a first-order rate expression. However, this model can also be reduced to give the same functional form as the classical Noyes-Whitney equation, in order to accurately fit/describe dissolution profiles which appear logarithmic (such profiles are due to dissolution phenomena that are not dispersive; i.e. for cases where the activation energy is essentially single-valued). Thus, the kinetic model presented in this work may potentially find broad applicability to the modeling of various dissolution trends observed in the literature.


Asunto(s)
Antibacterianos/química , Modelos Químicos , Norfloxacino/química , Cinética , Modelos Estadísticos , Solubilidad
19.
J Pharm Biomed Anal ; 41(3): 883-90, 2006 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-16524680

RESUMEN

The solution-phase hydrolysis kinetics of the Aprepitant (Emend) prodrug, Fosaprepitant Dimeglumine, were investigated using an HPLC chromatographic reactor approach. The term 'chromatographic reactor' refers to the use of an analytical-scale column as both a flow-through reactor and, simultaneously, as separation medium for the reactant(s) and product(s). Recently, we reported a novel mathematical treatment for the kinetic data obtained from chromatographic reactors, which we believe is superior to other treatments in terms of its accuracy, robustness and ease of implementation. In this work, we demonstrate that our treatment may be applied equally well to HPLC reactors, as previously we studied only GC reactors. It is found that the hydrolysis of Fosaprepitant Dimeglumine (FD) has an apparent activation energy of 107 kJ/mol when the reaction is investigated on-column, using the gradient elution conditions of the validated HPLC impurity profile method for this compound. For comparison, the activation energy determined for the same reaction occurring in a quiescent solution consisting of a fixed ratio of acetonitrile-0.1% v/v aqueous H3PO4 (50:50, v/v) is 91 kJ/mol, calculated using direct application of the Arrhenius equation. The data presented show that, when used as a screening tool, chromatographic reactors may be feasible for use in the pharmaceutical industry to quickly gauge the relative stabilities of various compounds with similar degradation pathways.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Preparaciones Farmacéuticas/química , Hidrólisis , Cinética , Termodinámica
20.
J Pharm Sci ; 105(9): 2625-2630, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27372548

RESUMEN

Use of amorphous phases can mitigate the low in vivo exposures of poorly soluble, crystalline active pharmaceutical ingredients. However, it remains challenging to accurately predict the solubility enhancement offered even by a pure amorphous phase relative to the crystalline form. In this work, a methodology is presented that allows estimation of the amorphous:crystalline solubility ratio, α, using only measured thermodynamic quantities for each of the pure phases. With this approach, α values of 7.6 and 4.7 were calculated for indomethacin and felodipine, respectively, correlating more closely than previous predictions with the experimentally measured values of 4.9 and 4.7 reported in the literature. There are 3 key benefits to this approach. First, it uses simple mathematical functions to more precisely relate the temperature variations in the heat capacity (Cp) to allow a more accurate estimation of the configurational energy difference between the 2 phases, whereas traditional models typically assume that Cp of both phases are constant(s). Second, the Hoffman equation is leveraged in translating the free energy of crystal lattice formation to the actual temperature of interest (selected to be 25°C/298K in this work), again, for better accuracy. Finally, as only 2 modulated differential scanning calorimetry scans are required (one for each phase), it is attractive from an experimental simplicity standpoint.


Asunto(s)
Felodipino/química , Indometacina/química , Modelos Químicos , Química Farmacéutica , Cristalización , Solubilidad , Termodinámica
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