Drug Solubilization Behavior During in Vitro Digestion of Simple Triglyceride Lipid Solution Formulations

PURPOSE: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during digestion of either long-chain or medium-chain triglyceride (TG) lipid formulations. METHODS: TG solution formulations of five selected drugs (griseofulvin, diazepam, danazol, cinnarizine, and halofantrine) were digested in ritro and drug distribution/solubilization behavior in the resulting digests assessed. RESULTS: For the less lipophilic drugs, the mass of drug dissolved in either medium or long-chain TG was low and the drugs partitioned rapidly into the aqueous digestion phase. For the higher log P drugs, drug transfer to the aqueous phase was limited by accumulation in undigested long-chain TG. In contrast, medium-chain TG was digested completely producing a dispersed aqueous phase that was capable, at least in the case of the high log P drugs, of supporting supersaturated drug concentrations. CONCLUSIONS: The solubilization behavior of lipophilic drugs on digestion of simple TG lipid formulations is a function of the lipophilicity of the drug (which dictates the drug dose and the partitioning behavior), the nature of the colloidal phases produced on digestion of the different formulation lipids, and the kinetics of drug transfer between the digesting formulation and the colloidal phases produced.     

The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations

An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico-chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed.     

Drug Solubilization Behavior During in Vitro Digestion of Suspension Formulations of Poorly Water-Soluble Drugs in Triglyceride Lipids

PURPOSE: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during the in vitro digestion of long-chain or medium-chain triglyceride (TG) lipid suspension formulations. METHODS: TG suspensions of model drugs (present at double their equilibrium solubilities in the respective lipid) were digested in vitro and the drug solubilization and precipitation pattern in the resulting digests analyzed. RESULTS: For griseofulvin, diazepam, and danazol, solubilization of the small mass of drug originally presented in the TG lipid was efficient with only a small proportion of the dose precipitating and being recovered in the pellet phase after digestion of the TG lipid. For the more lipophilic and lipid-soluble drugs (cinnarizine, halofantrine), in which higher drug loadings were possible, significant enhancement in drug solubilization in the postdigestion aqueous phase was not apparent compared with simple TG lipid solutions. CONCLUSIONS: Suspensions of drugs, which are poorly soluble in water and TG lipid, may prove beneficial as the relatively high solubilizing capacity of the colloidal phases produced on TG digestion will likely exceed the mass of drug that could have been administered as a simple lipid solution. However, for more lipid-soluble drugs, suspension formulations may offer little benefit as sufficiently high drug loadings can otherwise be achieved with simple solution formulations that still provide for adequate solubilization after TG digestion.     

Colorimetric Polymer Films for Predicting Lipid Interactions and Percutaneous Adsorption of Pharmaceutical Formulations

Purpose  To develop and demonstrate a rapid and simple colorimetric film assay for evaluating lipid interactions of pharmaceutical compounds and gel formulations. Methods  The colorimetric assay comprises glass-supported films of phospholipids and polydiacetylene, which undergo visible and quantifiable blue–red transformations induced by interactions with amphiphilic molecules applied in very small volumes on the film surface. The color transitions are recorded by scanning of the films, and quantified through a simple image analysis algorithm. Results  We show that pharmaceutical molecules and gel formulations induce blue–red transformations after short incubation with the lipid/polydiacetylene (PDA) films. Colorimetric dose–response curves exhibit dependence upon the lipid affinity and extent of membrane binding of the pharmaceutical compounds examined. The colorimetric lipid/PDA film assay was employed for distinguishing the contributions of individual molecular components within gel formulations. Conclusions  The colorimetric data yield insight into the degree of lipid binding of the molecules tested. The film assay is particularly advantageous for analysis of semi-solid (gel or lotion) formulations, elucidating the lipid interaction characteristics of specific molecular components within the mixtures. The new colorimetric film assay constitutes a generic, rapid, and easily applicable platform for predicting and screening interactions of pharmaceutical compounds and complex formulations with lipid barriers. Izek Ben-Shlush and Roman Volinsky contributed equally.     

Molecular Modeling of P-Glycoprotein and Related Drugs

This paper summarizes the results from molecular modeling of various multidrug resistance (MDR) modulators and the MDR protein P-glycoprotein (P-gp). Highly predictive 3D-QSAR models are obtained that can be used for anti-MDR activity prediction. The pharmacophore patterns of various drugs are identified. Models of P-gp are developed and a hypothesis for P-gp functioning is proposed.     

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drugs: Precipitation of Drug after Dispersion of Formulations in Aqueous Solution

This study was designed to investigate the precipitation of a lipophilic drug following dispersion of lipid formulations in water. The model drug fenofibrate was formulated in representative lipid delivery systems designed for oral administration, using medium chain glycerides, polysorbates, and propylene glycol as excipients. Aqueous dispersion of water-insoluble self-emulsifying lipid formulations resulted in turbid emulsions, followed subsequently by very slow precipitation of 3–7% of the dose of fenofibrate. Self-emulsifying formulations that included water-soluble surfactants, which dissolved a lower mass of drug in solution at equilibrium, nevertheless typically maintained drugs in a metastable state, following dilution with water, for several hours or even days. Formulations with higher contents of hydrophilic materials resulted in more rapid precipitation. Extensive precipitation of fenofibrate from oil-free formulations, comprising of only surfactants and cosolvents, took place within 30 min. The results indicated that most of the lipid systems were supersaturated with respect to the drug on dilution, but the extent of precipitation varied significantly between formulations and was influenced by the extent of supersaturation after dilution. The study suggests that the use of hydrophilic formulations for delivery of lipophilic drugs may result in a greater extent of drug precipitation in the stomach. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3582–3595, 2009     

Molecular Dynamics Simulation of Amorphous Indomethacin-Poly(Vinylpyrrolidone) Glasses: Solubility and Hydrogen Bonding Interactions

Amorphous drug dispersions are frequently employed to enhance solubility and dissolution of poorly water-soluble drugs and thereby increase their oral bioavailability. Because these systems are metastable, phase separation of the amorphous components and subsequent drug crystallization may occur during storage. Computational methods to determine the likelihood of these events would be very valuable, if their reliability could be validated. This study investigates amorphous systems of indomethacin (IMC) in poly(vinylpyrrolidone) (PVP) and their molecular interactions by means of molecular dynamics (MD) simulations. IMC and PVP molecules were constructed using X-ray diffraction data, and force-field parameters were assigned by analogy with similar groups in Amber-ff03. Five assemblies varying in PVP and IMC composition were equilibrated in their molten states then cooled at a rate of 0.03 K/ps to generate amorphous glasses. Prolonged aging dynamic runs (100 ns) at 298 K and 1 bar were then carried out, from which solubility parameters, the Flory-Huggins interaction parameter, and associated hydrogen bonding properties were obtained. Calculated glass transition temperature (T_g) values were higher than experimental results because of the faster cooling rates in MD simulations. Molecular mobility as characterized by atomic fluctuations was substantially reduced below the T_g with IMC–PVP systems exhibiting lower mobilities than that found in amorphous IMC, consistent with the antiplasticizing effect of PVP. The number of IMC–IMC hydrogen bonds (HBs) formed per IMC molecule was substantially lower in IMC–PVP mixtures, particularly the fractions of IMC molecules involved in two or three HBs with other IMC molecules that may be potential precursors for crystal growth. The loss of HBs between IMC molecules in the presence of PVP was largely compensated for by the formation of IMC–PVP HBs. The difference (6.5 MPa^1/2) between the solubility parameters in amorphous IMC (25.5 MPa^1/2) and PVP (19.0 MPa^1/2) suggests a small, positive free energy of mixing, although it is close to the criterion for miscibility (< 7 MPa^1/2). In contrast to the solubility-parameter method, the calculated Flory-Huggins interaction parameter (? 0.61 ± 0.25), which takes into account the IMC–PVP interaction energy, predicts complete miscibility at all PVP compositions, in agreement with experimental observations. These results from MD simulations were combined with experimental values for the crystalline γ-polymorph of IMC and amorphous IMC to estimate the solubility of IMC in amorphous PVP dispersions and the theoretical enhancement in the aqueous solubility of IMC molecularly dispersed in PVP at various volume fractions. © 2012Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:876–891, 2013     

Spectroscopic Characterization of Interactions Between PVP and Indomethacin in Amorphous Molecular Dispersions

Purpose. To study the molecular structure of indomethacin-PVP amorphous solid dispersions and identify any specific interactions between the components using vibrational spectroscopy. Methods. Solid dispersions of PVP and indomethacin were prepared using a solvent evaporation technique and IR and FT-Raman spectra were obtained. Results. A comparison of the carbonyl stretching region of indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of indomethacin is not as dimers. Addition of PVP to amorphous indomethacin increased the intensity of the infrared band assigned to non-hydrogen bonded carbonyl. Con-comitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a solution of indomethacin in methylpyrrolidone at the same weight percent. Conclusions. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystallisation kinetics by preventing the self association of indomethacin molecules. The similarity of results for solid dispersions and solutions emphasises the 'solution' nature of this binary amorphous state.     

The Effect of Excipients on the Molecular Mobility of Lyophilized Formulations,as Measured by Glass Transition Temperature and NMR Relaxation-Based Critical Mobility Temperature

Purpose. The dependence of the molecular mobility of lyophilized formulations on pharmaceutical polymer excipients was studied. Molecular mobility as determined by NMR relaxation-based critical temperature of molecular mobility (T_mc) and glass transition temperature (T_g) is discussed in relation to the plasticizing effect of water in formulations. Methods. The T_mc and T_g of lyophilized -globulin formulations containing 6 different polymer excipients such as dextran, polyvinylpyrrolidone (PVP) and methylcellulose (MC) was determined by NMR and DSC. The molecular mobility of water in the formulations was determined by proton NMR and dielectric relaxation spectrometry (DRS). Results. T_mc varied with polymer excipients. T_mc increased as the ratio of bound water to mobile water increased and as the molecular mobility of mobile water decreased. The formulation containing MC exhibited a lower T_mc than the formulation containing dextran because of the smaller ratio of bound water and the higher molecular mobility of mobile water. The T_mc of the formulation containing PVP was higher than that expected from the higher T₂ values of water because of the lower molecular mobility of mobile water regardless of the higher ratio of mobile water. The T_mc of these lyophilized formulations was higher than their T_g by 23°C to 34°C, indicating that the formulations became a NMR-detected microscopically liquidized state below their T_g. Conclusions. The quantity and the molecular mobility of mobile water in lyophilized formulations can be considered to affect the T_mc of lyophilized formulations, which in turn governs their stability.     

Pharmacokinetic Modeling and Simulation of Gastrointestinal Transit Effects on Plasma Concentrations of Drugs from Mixed Immediate-Release and Enteric-Coated Pellet Formulations

Effects of gastrointestinal transit on plasma concentrations of drugs from mixed immediate–release and enteric-coated pellet formulation were simulated with models developed by including gastric emptying time and lag time of emptying. Models were evaluated by comparing simulated plasma concentrations of amphetamine from Monte Carlo simulations to available published data of a commercial mixed pellet formulation (Adderall XR?). Results show that the plasma profile from the mixed pellet formulation does not mimic that from two immediate-release doses administered at different times. Instead, the plasma profile from the mixed pellets of amphetamine is similar to a typical sustained-release formulation. The pharmacokinetic models presented herein describe plasma concentrations of amphetamine from mixed pellet formulation quite well. The models and assumptions are general and can be applied to other drugs in similar mixed pellet dosage forms.     

Phase Behavior of Amorphous Molecular Dispersions II: Role of Hydrogen Bonding in Solid Solubility and Phase Separation Kinetics

No HeadingPurpose. To determine the factors influencing solid solubility and phase separation kinetics of drugs from amorphous solid dispersions.Methods. Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single T_g were exposed to 40°C/69% RH for 90 days. Drug solid solubility in the polymer and phase separation rates were determined from changes in T_g of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively.Results. Freshly prepared solid dispersion of up to 30% w/w griseofulvin and indoprofen were molecularly miscible with PVP. Hydrogen bonding was evident in indoprofen-PVP, but not in griseofulvin-PVP dispersions. When exposed to 40°C/69% RH, griseofulvin phase separated completely, whereas the solid solubility of indoprofen was determined as 13% w/w. The first-order rate constants of phase separation for 10%. 20%, and 30% w/w griseofulvin dispersions were estimated as 4.66, 5.19, and 12.50 (×10²) [day^–1], and those of 20% and 30% w/w indoprofen were 0.62 and 1.25 (×10²) [day^–1], respectively.Conclusions. Solid solubility of griseofulvin and indoprofen in PVP is 0% w/w and 13% w/w, respectively. Drug-polymer hydrogen bonding in indoprofen-PVP dispersions favors solid solubility. Phase separation rate of drug from the solid dispersions depends on the initial drug content and the nature of drug-polymer interactions.     

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations

Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by ¹H-NMR. Thermal properties were assessed by differential scanning calorimetry and hot-stage microscopy. X-ray diffraction and polarized light microscopy were used to confirm the salt's physical form. All lipophilic salt forms were substantially more lipid-soluble (typically >10-fold) when compared to commercial salts. For example, amlodipine concentrations in lipidic excipients were limited to <5-10 mg/g when using the besylate salt but could be increased to >100 mg/g when using the docusate salt. Higher lipid solubility of the lipophilic salts of each drug translated to higher drug loadings in lipid formulations. In vitro tests showed that lipophilic salts solubilized in a lipid formulation resulted in dispersion behavior that was at least as rapid as the dissolution rates of conventional salts. This study confirmed the applicability of forming lipophilic salts of BCS I and III drugs to promote the utility of lipid-based delivery systems.     

Modeling and Monitoring of Polymorphic Transformations During the Drying Phase of Wet Granulation

PURPOSE: The purpose of this work was to monitor polymorphic transformations of glycine during the drying phase of a wet granulation and model the polymorphic conversions using a time-based reconciliation model. METHODS: Near-infrared spectroscopy (NIR) was used for quantitation of polymorphs, and X-ray powder diffraction (XRPD) was used for qualitative analysis of polymorphs. RESULTS: The data show that the faster the granulation was dried, the more kinetic trapping of the metastable alpha-glycine polymorph, as predicted by reconciliation of the time scales of both the drying rate and the rate of the solution-mediated conversion. CONCLUSIONS: By knowing basic properties of the drug substance (solubility of the polymorphic forms and the rate of the solution-mediated conversion), processing conditions, such as the drying rate, can be adjusted to anticipate and prevent potential polymorphic transformations.     

Electrostatically Mediated Protein-Protein Interactions for Monoclonal Antibodies: A Combined Experimental and Coarse-Grained Molecular Modeling Approach

Electrostatically mediated protein-protein interactions (PPI) can influence key product properties such as solubility, solution viscosity, and aggregation rates. Predictive models would allow for candidates/formulations to be screened with little or no protein material. Three monoclonal antibodies that display qualitatively different experimental PPI were evaluated at a range of pH and ionic strength conditions that are typical of product formulations. PPI parameters (k_D, B₂₂, and G₂₂) were obtained from static and dynamic light scattering measurements and spanned from strongly repulsive to strongly attractive net interactions. Coarse-grained (CG) molecular simulations of PPI (specifically, B₂₂) were compared against experimental PPI parameters across multiple pH and salt conditions, using a CG model that treats each amino acid explicitly. Predicted B₂₂ values with default model parameters matched experimental B₂₂ values semiquantitatively for some cases; others required parameter tuning to account for effects such as ion binding. Experimental PPI values were also analyzed for each monoclonal antibody within the context of single-protein properties such as net charge, and domain-based and global dipole moments. The results show that PPI predicted qualitatively and semiquantitatively by CG molecular modeling of B₂₂ can be an effective computational tool for molecule and formulation assessment.     

Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats

Purpose This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA and plasma lipids associated with increased risks for atherosclerosis. Materials and methods Normal male Wistar rats were given 50 mg/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA, and plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG). Results MPL showed bi-exponential disposition with two first-order absorption components. Hepatic GR and LDLR mRNA exhibited circadian patterns which were disrupted by MPL. Down-regulation in GR mRNA (40–50%) was followed by a delayed rebound phase. LDLR mRNA exhibited transient down-regulation (60–70%). Cytosolic GR density was significantly suppressed but returned to baseline by 72 h. Plasma TC and LDLC showed increases (55 and 142%) at 12 h. A mechanistic receptor/gene pharmacokinetic/pharmacodynamic model was developed to describe CS effects on hepatic LDLR mRNA and plasma cholesterols. Conclusions Our PK/PD model was able to satisfactorily capture the MPL effects on hepatic LDLR, its relationship to various plasma cholesterols, and builds the foundation to explore this area in the future. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

医生处方行为干预与使用国家基本药物的相关性

对医生处方进行调查，并采取一定形式的干预行为，如向医生调查了解有关基本药物的知识、反馈信息、编发基本药物专刊、举办讲座等，评价该行动与使用国家基本药物的相关性。     

Liposomal Formulations of Cyclosporin A: Influence of Lipid Type and Dose on Pharmacokinetics

Purpose. Liposomal formulations of Cyclosporin A (CyA)³ have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics. Methods. A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood. Results. Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood. Conclusions. These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.     

Predicting Inter-individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study

IntroductionIntravenous lipid emulsions (ILE) have been credited for successful resuscitation in drug intoxication cases where other cardiac life-support methods have failed. However, inter-individual variability can function as a confounder that challenges our ability to define the scope of efficacy for lipid interventions, particularly as relevant data are scarce. To address this challenge, we developed a quantitative systems pharmacology model to predict outcome variability and shed light on causal mechanisms in a virtual population of rats subjected to bupivacaine toxicity and ILE intervention.Materials and MethodsWe combined a physiologically based pharmacokinetic–pharmacodynamic model with data from a small study in Sprague-Dawley rats to characterize individual-specific cardiac responses to lipid infusion. We used the resulting individual parameter estimates to posit a population distribution of responses to lipid infusion. On that basis, we constructed a large virtual population of rats (N = 10,000) undergoing lipid therapy following bupivacaine cardiotoxicity.ResultsUsing unsupervised clustering to assign resuscitation endpoints, our simulations predicted that treatment with a 30% lipid emulsion increases bupivacaine median lethal dose (LD₅₀) by 46% when compared with a simulated control fluid. Prior experimental findings indicated an LD₅₀ increase of 48%. Causal analysis of the population data suggested that muscle accumulation rather than liver accumulation of bupivacaine drives survival outcomes.ConclusionOur results represent a successful prediction of complex, dynamic physiological outcomes over a virtual population. Despite being informed by very limited data, our mechanistic model predicted a plausible range of treatment outcomes that accurately predicts changes in LD₅₀ when extrapolated to putatively toxic doses of bupivacaine. Furthermore, causal analysis of the predicted survival outcomes indicated a critical synergy between scavenging and direct cardiotonic mechanisms of ILE action.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-021-00353-4.     

Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions

Purpose

To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems.

Methods

Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (T_g). ¹³C and ¹⁵N solid-state NMR was utilized to investigate changes in local structure and protonation state, while ¹H T₁ and T_1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions.

Results

T_g values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction. ¹⁵N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at ?360.7 ppm (unprotonated) and ?344.4 ppm (protonated). Additionally, ¹H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.

Conclusions

¹⁵N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.