RESUMEN
A graphical analysis of both drug and coformer concentrations contributed by dissolving cocrystals is presented in the context of a simplified cocrystal phase diagram. The conceptual basis and analysis identify parameters that control cocrystal dissolution-drug supersaturation-precipitation (DSP) behavior. The important effects of coformer concentration, cocrystal dose, and cocrystal solubility on drug supersaturation levels are demonstrated and quantified by the DSPindex. While the studies presented rely on high and nonstoichiometric coformer concentrations contributed by the dissolving cocrystals, the concepts and findings can answer the question of whether and how much coformer should be added to cocrystal dissolution media or formulations.
Asunto(s)
Solubilidad , Cristalización , Composición de MedicamentosRESUMEN
Two of the main questions regarding cocrystal selection and formulation development are whether the will be stable and how fast can it dissolve the drug dose. Dissolving the drug dose may require cocrystals with a high solubility advantage over drug (SA = SCC/SD), but these may have limited potential to sustain drug supersaturation. Thus, we propose a twofold approach to mitigate the risk of drug precipitation by optimizing thermodynamic (SA) and kinetic factors (nucleation inhibitors). This risk can be evaluated by considering the cocrystal SA and drug dose/solubility ratio (D0D = Cdose/SD), which in tandem represent the maximum theoretical supersaturation that a cocrystal may generate, the driving force for drug precipitation, and the potential for dose-/solubility-limited absorption. cocrystals with SA and D0D values above critical supersaturation are prone to rapid precipitation, often negating their utility as a solubility enhancement tool. This work presents a mechanistic approach to controlling the dissolution-supersaturation-precipitation behavior of cocrystal systems, whereby relationships between SA, D0D, and the drug-solubilizing power of surfactants (SPD = SD,T/SD,aq) are used to fine-tune cocrystal-inherent supersaturation by rational additive selection. Experimental results with danazol-vanillin cocrystal demonstrate how SA, D0D, and SPD are key thermodynamic parameters to understanding the kinetic cocrystal behavior and how the risks of cocrystal development may be mitigated through the mechanistic formulation design.
Asunto(s)
Benzaldehídos/química , Precipitación Química/efectos de los fármacos , Danazol/química , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Tensoactivos/química , Benzaldehídos/farmacología , Cristalización , Liberación de Fármacos/efectos de los fármacos , Concentración de Iones de Hidrógeno , Cinética , Solubilidad/efectos de los fármacos , Tensoactivos/farmacología , TemperaturaRESUMEN
Cocrystals are often more soluble than needed and pose unnecessary risks for precipitation of less soluble forms of the drug during processing and dissolution. Such conversions lead to erratic cocrystal behavior and nullify the cocrystal solubility advantage over parent drug (SA = Scocrystal/Sdrug). This work demonstrates a quantitative method for additive selection to control cocrystal disproportionation based on cocrystal solubility advantage (SA) diagrams. The tunability of cocrystal SA is dependent on the selective drug-solubilizing power of surfactants (SPdrug = (ST/Saq)drug). This cocrystal property is used to generate SA-SP diagrams that facilitate surfactant selection and provide a framework for evaluating how SA influences drug concentration-time profiles associated with cocrystal dissolution, drug supersaturation, and precipitation (DSP). Experimental results with indomethacin-saccharin cocrystal and surfactants (sodium lauryl sulfate, Brij, and Myrj) demonstrate the log-linear relationship characteristic of SA-SP diagrams and the dependence of σmax and dissolution area under the curve (AUC) on SA with characteristic maxima at a threshold supersaturation where drug nucleation occurs. This approach is expected to streamline cocrystal formulation as it facilitates additive selection by considering the interplay between thermodynamic (SA) and kinetic (DSP) processes.
Asunto(s)
Precipitación Química , Liberación de Fármacos , Indometacina/química , Aceites de Plantas/química , Polietilenglicoles/química , Sacarina/química , Dodecil Sulfato de Sodio/química , Tensoactivos/química , Área Bajo la Curva , Cristalización , Concentración de Iones de Hidrógeno , Cinética , Concentración Osmolar , Solubilidad , TemperaturaRESUMEN
The goal of this project was to explore and to statistically evaluate the responsible gastrointestinal (GI) factors that are significant factors in explaining the systemic exposure of ibuprofen, between and within human subjects. In a previous study, we determined the solution and total concentrations of ibuprofen as a function of time in aspirated GI fluids, after oral administration of an 800 mg IR tablet (reference standard) of ibuprofen to 20 healthy volunteers in fasted state conditions. In addition, we determined luminal pH and motility pressure recordings that were simultaneously monitored along the GI tract. Blood samples were taken to determine ibuprofen plasma levels. In this work, an in-depth statistical and pharmacokinetic analysis was performed to explain which underlying GI variables are determining the systemic concentrations of ibuprofen between (inter-) and within (intra-) subjects. In addition, the obtained plasma profiles were deconvoluted to link the fraction absorbed with the fraction dissolved. Multiple linear regressions were performed to explain and quantitatively express the impact of underlying GI physiology on systemic exposure of the drug (in terms of plasma Cmax/AUC and plasma Tmax). The exploratory analysis of the correlation between plasma Cmax/AUC and the time to the first phase III contractions postdose (TMMC-III) explains â¼40% of the variability in plasma Cmax for all fasted state subjects. We have experimentally shown that the in vivo intestinal dissolution of ibuprofen is dependent upon physiological variables like, in this case, pH and postdose phase III contractions. For the first time, this work presents a thorough statistical analysis explaining how the GI behavior of an ionized drug can explain the systemic exposure of the drug based on the individual profiles of participating subjects. This creates a scientifically based and rational framework that emphasizes the importance of including pH and motility in a predictive in vivo dissolution methodology to forecast the in vivo performance of a drug product. Moreover, as no extensive first-pass metabolism is considered for ibuprofen, this study demonstrates how intraluminal drug behavior is reflecting the systemic exposure of a drug.
Asunto(s)
Liberación de Fármacos , Ayuno/fisiología , Absorción Gastrointestinal/fisiología , Tracto Gastrointestinal/fisiología , Ibuprofeno/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Variación Biológica Individual , Variación Biológica Poblacional/fisiología , Conjuntos de Datos como Asunto , Femenino , Voluntarios Sanos , Humanos , Concentración de Iones de Hidrógeno , Ibuprofeno/administración & dosificación , Masculino , Persona de Mediana Edad , Modelos Biológicos , Solubilidad , Comprimidos , Adulto JovenRESUMEN
PURPOSE: Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo. METHODS: First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune cell subpopulations of different organs. Second, to further investigate the mechanism of CLDI formation, we asked whether specific accumulation of CFZ hydrochloride crystals in lysosomes could be explained as a passive, thermodynamic equilibrium phenomenon. A cellular pharmacokinetic model was constructed, simulating CFZ accumulation driven by pH-dependent ion trapping of the protonated drug in the acidic lysosomes, followed by the precipitation of CFZ hydrochloride salt via a common ion effect caused by high chloride concentrations. RESULTS: While lower loads of CFZ were mostly accommodated in lung macrophages, increased CFZ loading was accompanied by organ-specific changes in macrophage numbers, size and intracellular membrane architecture, maximizing the cargo storage capabilities. With increasing loads, the total cargo mass and concentrations of CFZ in different organs diverged, while that of individual macrophages converged. The simulation results support the notion that the proton and chloride ion concentrations of macrophage lysosomes are sufficient to drive the massive, cell type-selective accumulation and growth of CFZ hydrochloride biocrystals. CONCLUSION: CLDIs effectively function as an expandable mechanopharmaceutical device, revealing the coordinated response of the macrophage population to an increasingly massive, whole-organism endophagolysosomal cargo load.
Asunto(s)
Antibacterianos/farmacocinética , Clofazimina/farmacocinética , Macrófagos/metabolismo , Animales , Transporte Biológico , Línea Celular , Membrana Celular/metabolismo , Simulación por Computador , Portadores de Fármacos/química , Liberación de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Tamaño de la Partícula , Aceite de Sésamo , Solubilidad , SolventesRESUMEN
Although magic-angle-spinning (MAS) solid-state NMR spectroscopy has been able to provide piercing atomic-level insights into the structure and dynamics of various solids, the poor sensitivity has limited its widespread application, especially when the sample amount is limited. Herein, we demonstrate the feasibility of acquiring high S/N ratio natural-abundance 13 Câ NMR spectrum of a small amount of sample (≈2.0â mg) by using multiple-contact cross polarization (MCP) under ultrafast MAS. As shown by our data from pharmaceutical compounds, the signal enhancement achieved depends on the number of CP contacts employed within a single scan, which depends on the T1ρ of protons. The use of MCP for fast 2D 1 H/13 C heteronuclear correlation experiments is also demonstrated. The significant signal enhancement can be greatly beneficial for the atomic-resolution characterization of many types of crystalline solids including polymorphic drugs and nanomaterials.
Asunto(s)
Ibuprofeno/química , Nanoestructuras/química , Espectroscopía de Resonancia Magnética con Carbono-13RESUMEN
The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid-liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals.
Asunto(s)
Carbamazepina/química , Sacarina/química , Ácido Salicílico/química , Termodinámica , Rastreo Diferencial de Calorimetría , Cristalización , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Micelas , Difracción de Polvo , Solubilidad , Difracción de Rayos XRESUMEN
In this manuscript we bring together concepts that are relevant to the solubilization and thermodynamic stability of cocrystals in the presence of drug solubilizing agents. Simple equations are derived that allow calculation of cocrystal solubilization and transition point solubility. Analysis of 10 cocrystals in 6 different solubilizing agents shows that cocrystal solubilization is quantitatively predicted from drug solubilization. Drug solubilizing agents such as surfactants and lipid-based media are also shown to induce cocrystal transition points, where drug and cocrystal solubilities are equal, and above which the cocrystal solubility advantage over drug is eliminated. We have discovered that cocrystal solubility at the transition point (S*) is independent of solubilizing agent, and can be predicted from knowledge of only the aqueous solubilities of drug and cocrystal. For 1:1 cocrystals, S* = (Scocrystal,aq)(2)/Sdrug,aq. S* is a key indicator of cocrystal thermodynamic stability and establishes the upper solubility limit below which cocrystal is more soluble than the constituent drug. These findings have important implications to tailor cocrystal solubility and stability in pharmaceutical formulations from commonly available drug solubility descriptors.
Asunto(s)
Cristalización , Preparaciones Farmacéuticas/química , Estabilidad de Medicamentos , Lípidos/química , Solubilidad , Tensoactivos/química , TermodinámicaRESUMEN
In mammals, highly lipophilic small molecule chemical agents can accumulate as inclusions within resident tissue macrophages. In this context, we characterized the biodistribution, chemical composition, and structure of crystal-like drug inclusions (CLDIs) formed by clofazimine (CFZ), a weakly basic lipophilic drug. With prolonged oral dosing, CFZ exhibited a significant partitioning with respect to serum and fat due to massive bioaccumulation and crystallization in the liver and spleen. The NMR, Raman, and powder X-ray diffraction (p-XRD) spectra of CLDIs isolated from the spleens of CFZ-treated mice matched the spectra of pure, CFZ hydrochloride crystals (CFZ-HCl). Elemental analysis revealed a 237-fold increase in chlorine content in CLDIs compared to untreated tissue samples and a 5-fold increase in chlorine content compared to CFZ-HCl, suggesting that the formation of CLDIs occurs through a chloride mediated crystallization mechanism. Single crystal analysis revealed that CFZ-HCl crystals had a densely packed orthorhombic lattice configuration. In vitro, CFZ-HCl formed at a pH of 4-5 only if chloride ions were present at sufficiently high concentrations (>50:1 Cl(-)/CFZ), indicating that intracellular chloride transport mechanisms play a key role in the formation of CLDIs. While microscopy and pharmacokinetic analyses clearly revealed crystallization and intracellular accumulation of the drug in vivo, the chemical and structural characterization of CLDIs implicates a concentrative, chloride transport mechanism, paralleling and thermodynamically stabilizing the massive bioaccumulation of a weakly basic drug.
Asunto(s)
Transporte Biológico/efectos de los fármacos , Clofazimina/metabolismo , Clofazimina/farmacología , Animales , Cloruros/metabolismo , Cristalización/métodos , Cuerpos de Inclusión , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/metabolismo , Distribución TisularRESUMEN
Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.
Asunto(s)
Carbamazepina/química , Indometacina/química , Sacarina/química , Rastreo Diferencial de Calorimetría/métodos , Cristalización/métodos , Concentración de Iones de Hidrógeno , Modelos Químicos , Difracción de Polvo/métodos , Solubilidad , Agua/química , Difracción de Rayos X/métodosRESUMEN
Despite its high efficacy and good patient compliance, the only long-acting injectable (LAI) contraceptive currently available in the US, depot medroxyprogesterone acetate (DMPA), is limited by significant side effects and a delayed return to fertility for up to 10 months after its intended duration of action. To overcome these limitations, we sought to develop an injectable poly(D,l-lactide) (PLA) microparticle for sustained release of contraceptive hormone, etonogestrel (ENG). A one-step technique, coaxial electrospray method was applied to prepare uniform ENG loaded core-shell structured and slow-degrading PLA microparticles (ENG-cs-MPs) to provide release control while minimizing polymer content. By adjusting voltage, polymer concentration and flow rate of the coaxial jetting solution, the prepared ENG-cs-MPs exhibited uniformly small particle size with volume mean diameter of 14.7 ± 0.5 µm and a shell thickness of 2.5 ± 0.1 µm, high drug loading of ~54%, high encapsulation efficiency of ~99%, and initial 1-day burst release of just ~10%. Long-term in vitro release of ENG was continuous for more than 3 months without change of the shell structure in 6 months. In PK studies, ENG-cs-MPs achieved a steady and continuous drug release for approximately 3 months and then quickly tapered off within 3 weeks. Hence, ENG-cs-MPs prepared by the coaxial electrospray method may be useful as a LAI contraceptive with an improved PK profile relative to DMPA.
Asunto(s)
Anticonceptivos , Poliésteres , Liberación de Fármacos , Humanos , Tamaño de la Partícula , Poliésteres/químicaRESUMEN
Knowledge of the stability of pharmaceutical formulations against relative humidity (RH) is essential if they are to become pharmaceutical products. The increasing interest in formulating active pharmaceutical ingredients as stable co-crystals (CCs) triggers the need for fast and reliable in-silico predictions of CC stability as a function of RH. CC storage at elevated RH can lead to deliquescence, which leads to CC dissolution and possible transformation to less soluble solid-state forms. In this work, the deliquescence RHs of the CCs succinic acid/nicotinamide, carbamazepine/nicotinamide, theophylline/citric acid, and urea/glutaric acid were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These deliquescence RH values together with predicted phase diagrams of CCs in water were used to determine critical storage conditions, that could lead to CC instability, that is, CC dissolution and precipitation of its components. The importance of CC phase purity on RH conditions for CC stability is demonstrated, where trace levels of a separate phase of active pharmaceutical ingredient or of coformer can significantly decrease the deliquescence RH. The use of additional excipients such as fructose or xylitol was predicted to decrease the deliquescence RH even further. All predictions were successfully validated by stability measurements at 58%, 76%, 86%, 93%, and 98% RH and 25 °C.
RESUMEN
Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=Cdose/Sdrug), cocrystal solubility advantage over drug (SA=Scocrystal/Sdrug), and dissolution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and Ksp values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pHint) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (σmax=Cmax/Sdrug)and AUC increased with increasing Do as pH decreased. When Do>>SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution-precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Do<Asunto(s)
Solubilidad
, Cristalización
, Liberación de Fármacos
, Concentración de Iones de Hidrógeno
, Meloxicam
RESUMEN
The dissolution behavior of a dibasic drug ketoconazole under the influence of pH has been evaluated and compared to its three 1:1 cocrystals with diacidic coformers, fumaric acid, succinic acid (SUC), and adipic acid. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving surface to predict the interfacial pH and flux of the parent drug and cocrystals. All 3 cocrystals have the ability to modulate the interfacial pH to different extents compared to the parent drug due to the acidity of the coformers. Dissolution pH dependence of ketoconazole is significantly reduced by the cocrystallization with acidic coformers. Due to the different dissolution pH dependence, there exists a transition pH where the flux of the cocrystal is the same as the parent drug. Below this transition pH, the drug flux is higher, but above it, the cocrystal flux is higher. The development of these mass transport models provide a mechanistic understanding of the dissolution behavior and help identify cocrystalline solids with optimal dissolution characteristics.
Asunto(s)
Adipatos/química , Composición de Medicamentos/métodos , Fumaratos/química , Cetoconazol/química , Modelos Químicos , Ácido Succínico/química , Cristalización , Concentración de Iones de Hidrógeno , Solubilidad , Propiedades de SuperficieRESUMEN
The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt-Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma Cmax and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.01 N hydrochloric acid and 34 mM sodium chloride as the gastric medium and fasted state simulated intestinal fluids (FaSSIF-v1) as the intestinal medium showed a faster rate and a higher extent of dissolution of the non-BE product compared to the BE and reference products. These in vitro profiles mirrored the fraction doses absorbed in vivo obtained from deconvoluted plasma concentrationâ»time profiles. However, when sodium chloride was not included in the gastric medium and phosphate buffer without bile salts and phospholipids were used as the intestinal medium, the three products exhibited nearly identical concentration profiles. Microscopic examination of DKT salt dissolution in the gastric medium containing sodium chloride identified that when calcium phosphate was present, the DKT dissolved without conversion to the less soluble free acid, which was consistent with the higher drug exposure of the non-BE formulation. In the absence of calcium phosphate, however, dexketoprofen trometamol salt dissolution began with a nano-phase formation that grew to a liquidâ»liquid phase separation (LLPS) and formed the less soluble free acid crystals. This phenomenon was dependent on the salt/excipient concentrations and the presence of free acid crystals in the salt phase. This work demonstrated the importance of excipients and purity of salt phase on the evolution and rate of salt disproportionation pathways. Moreover, the presented data clearly showed the usefulness of the GIS apparatus as a discriminating tool that could highlight the differences in formulation behavior when utilizing physiologically-relevant media and experimental conditions in combination with microscopy imaging.
RESUMEN
Weakly basic drugs are predisposed to order of magnitude decreases in solubility and dissolution as pH increases from 1 to 7 along the gastrointestinal tract. Such behavior is known to be detrimental to drug absorption. The work presented here shows how cocrystals of basic drugs with acidic coformers can mitigate these negative effects. Cocrystals of ketoconazole (KTZ) with adipic, fumaric, and succinic acids exhibit a parabolic solubility dependence on pH such that with increasing pH, solubility decreases, reaches a minimum, and increases. Cocrystals exhibit pHmax values between 3.6 and 3.8, above which they generate supersaturation with respect to drug. Cocrystal supersaturation index (SA), defined as Scocrystal/Sdrug, changes from 1 (pHmax) to 10-30 (pH 5) to 800 - 3,000 (pH 6.5). SA represents the driving force for cocrystal conversion to the less soluble drug during dissolution. SA is not expected to be equal to the observed supersaturation, but it is of great value to classify cocrystals in terms of their risk of conversion. Cocrystal dissolution behavior was analyzed in terms of Cmax, σmax (maximum KTZ concentration and supersaturation), AUCdiss (KTZ concentration area under the curve during dissolution-precipitation), and SA. The three cocrystals studied achieved σmax values between 5 and 15 and sustained supersaturation for 1 to 3 h, resulting in AUCdiss advantage over drug in the range of 2 to 12. SA values as high as 800 were associated with enhanced drug exposure. SA of 3,000 led to limited exposure, very rapid conversion, and no measurable supersaturation. Since cocrystals may be more soluble than needed and/or too soluble to be developed, there is great value in recognizing the relationship between supersaturation threshold, cocrystal solubility, and SA. This becomes more important as cocrystal SA is dependent on pH and other environmental conditions.
RESUMEN
This work challenges the popular notion that pharmaceutical salts are more soluble than cocrystals. There are cocrystals that are more soluble than salt forms of a drug and vice-versa. It all depends on the interplay between the chemistry of both the solid and solution phases. Aqueous solubility, pHmax, and supersaturation index (SA = SCC/SD or Ssalt/SD) of cocrystals and salts of a basic drug, lamotrigine (LTG), were determined, and mathematical models that predict the influence of cocrystal/salt Ksp and Ka were derived. Ksp and SA followed the order LTG-nicotinamide cocrystal (18) > LTG-HCl salt (12) > LTG-saccharin salt (5) > LTG-methylparaben cocrystal (1) > LTG-phenobarbital cocrystal (0.2). The values in parenthesis represent SA under nonionizing conditions. Cocrystal/salt solubility and thermodynamic stability are determined by pH and will drastically change with a single unit change in pH. pHmax values ranged from 5.0 (saccharin salt) to 6.4 (methylparaben cocrystal) to 9.0 (phenobarbital cocrystal). Cocrystal/salt pHmax dependence on pKsp and pKa shows that cocrystals and salts exhibit different behavior. Solubility and pHmax are as important as supersaturation index in assessing the stability and risks associated with conversions of supersaturating forms.
Asunto(s)
Preparaciones Farmacéuticas/química , Sales (Química)/química , Agua/química , Cristalización/métodos , Concentración de Iones de Hidrógeno , Lamotrigina , Niacinamida/química , Sacarina/química , Solubilidad , Termodinámica , Triazinas/químicaRESUMEN
Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.
Asunto(s)
Carbamazepina/química , Sacarina/química , Ácido Salicílico/química , Cristalización/métodos , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Micelas , Solubilidad/efectos de los fármacos , Tensoactivos/química , TermodinámicaRESUMEN
Supersaturating drug delivery systems (SDDS) have been put forward in the recent decades in order to circumvent the issue of low aqueous solubility. Prior to the start of clinical trials, these enabling formulations should be adequately explored in in vitro/in silico studies in order to understand their in vivo performance and to select the most appropriate and effective formulation in terms of oral bioavailability and therapeutic outcome. The purpose of this work was to evaluate the in vivo performance of four different oral formulations of posaconazole (categorized as a biopharmaceutics classification system (BCS) class 2b compound) based on the in vitro concentrations in the gastrointestinal simulator (GIS), coupled with an in silico pharmacokinetic model to predict their systemic profiles. Recently published intraluminal and systemic concentrations of posaconazole for these formulations served as a reference to validate the in vitro and in silico results. Additionally, the morphology of the formed precipitate of posaconazole was visualized and characterized by optical microscopy studies and thermal analysis. This multidisciplinary work demonstrates an in vitro-in silico-in vivo approach that provides a scientific basis for screening SDDS by a user-friendly formulation predictive dissolution (fPD) device in order to rank these formulations towards their in vivo performance.
Asunto(s)
Tracto Gastrointestinal/metabolismo , Triazoles/química , Triazoles/metabolismo , Administración Oral , Disponibilidad Biológica , Biofarmacia/métodos , Química Farmacéutica/métodos , Simulación por Computador , Sistemas de Liberación de Medicamentos/métodos , Absorción Intestinal/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Solubilidad/efectos de los fármacosRESUMEN
A drug-drug cocrystal of two anticonvulsants, lamotrigine and phenobarbital, is presented. In the crystal structure, molecules form heterodimers via N-H···O and N-H···N hydrogen bonding. The intrinsic dissolution rate (IDR) and solubility of the cocrystal were measured in phosphate buffer (pH 7.2) and simulated gastric fluid (without pepsin), and compared to pure APIs. Dissolution experiments found suppressed IDR of the cocrystal with rates in the order pure PB > pure LTG > cocrystal. The solubility measurements were consistent with the dissolution behavior. The presence of strong heterodimers in the cocrystal compared to weaker homodimers in the parent drugs is implicated for the reduced solubility and dissolution rate.