Nicole Wyttenbach

Miniaturized screening of polymers for amorphous drug stabilization (SPADS): Rapid assessment of solid dispersion systems

PURPOSE Development of a novel, rapid, miniaturized approach to identify amorphous solid dispersions with maximum supersaturation and solid state stability. METHOD Three different miniaturized assays are combined in a 2-step decision process to assess the supersaturation potential and drug-polymer miscibility and stability of amorphous compositions. Step 1: SPADS dissolution assay. Drug dissolution is determined in 96-well plates to detect systems that generate and maintain supersaturation. Promising combinations graduate to step 2. Step 2: SPADS interaction and SPADS imaging assays. FTIR microspectroscopy is used to study intermolecular interactions. Atomic force microscopy is applied to analyze molecular homogeneity and stability. Based on the screening results, selected drug-polymer combinations were also prepared by spray-drying and characterized by classical dissolution tests and a 6-month physical stability study. RESULTS From the 7 different polymers and 4 drug loads tested, EUDRAGIT E PO at a drug load of 20% performed best for the model drug CETP(2). The classical dissolution and stability tests confirmed the results from the miniaturized assays. CONCLUSION The results demonstrate that the SPADS approach is a useful de-risking tool allowing the rapid, rational, time- and cost-effective identification of polymers and drug loads with appropriate dual function in supersaturation performance and amorphous drug stabilization.

Drug-Excipient Compatibility Testing Using a High-Throughput Approach and Statistical Design

The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of ~ 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40°C/50°C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.

Structured Development Approach for Amorphous Systems

A structured development approach is presented to guide the development of stable and commercially viable polymer based amorphous formulations. The proposed approach should not only enable the delivery of poorly soluble drugs but also help to reduce the API needs, reduce in vivo screening, minimize risks for late-stage development, and should ensure consistent quality. During initial assessment, a guided evaluation of the physicochemical properties of the API helps to assess the degree of difficulty for the development. A range of tests including in silico evaluation, high-throughput screening assays, and miniaturized screening tools provide a road map for selecting the appropriate polymer, drug loading, and suitable manufacturing process. A dedicated section provides a review of the characterization tools to assess and quantify the crystallinity, understanding the phase behavior of amorphous solid dispersions, and designing the in vitro dissolution methods. Finally, a reference chart is provided that summarizes the key concepts proposed as part of the structured development approach that can serve as a blueprint for the development of amorphous formulations. The current authors would like to thank and acknowledge the significant contribution of the previous authors of this chapter from the first edition. This current second edition chapter is a revision and update of the original authors’ work.

Application of a Statistical Method to the Absorption of a New Model Drug from Micellar and Lipid Formulations—Evaluation of Qualitative Excipient Effects

The scope of the present article is to study formulation parameters of micellar and of lipid delivery systems on the exposure of a new drug compound A in Wistar rats. A statistical analysis is to be performed a posteriori from a data set of all rat studies that were conducted during the preclinical development of the drug. Several formulations were evaluated mainly in view of sufficient exposure in toxicological studies. Because of the low solubility and high lipophilicity of compound A, the preclinical formulation development focused on micellar solutions and different kinds of lipid drug delivery systems. Candidate formulations were first tested for their dilution in artificial intestinal fluids before they were evaluated in the rat. A partial least square model was applied to the entire pharmacokinetic data set, and the type of delivery system, as well as excipients, were investigated in view of effects on the area under the plasma level curve. The results showed that self-emulsifying systems and in particular self-microemulsifying drug delivery systems were most effective in pushing the exposure of compound A. Another significant factor was the dose. A data subset showed nonlinearity in the pharmacokinetics with respect to the dose. However, the most important findings of the multivariate data analysis were overall effects of excipients on the exposure. These effects are considered as a sum of several influences so that the underlying mechanism is essentially complex and is not fully understood. Cremophor and lecithin exhibited a positive effect, whereas TPGS containing systems reached only below average exposure. No significant effect was observed with polysorbate 80 or Solutol HS. The model indicated the favorable use of a cosurfactant, in particular Capmul MCM. Similarly the use of a cosolvent showed a positive coefficient and ethanol was here best in class. No marked effects were observed for the oil selection, but a tendency toward below average exposure was displayed when long-chain triglycerides were in the formulation. The a posteriori analysis of the pharmacokinetic data using multivariate statistical models was very helpful to clarify effects of drug delivery systems as well as of general effects of excipients. Guidance was provided for the formulator, but further studies are needed to better understand the complex effects on a mechanistic level.

Theoretical Considerations of the Prigogine-Defay Ratio with Regard to the Glass-Forming Ability of Drugs from Undercooled Melts.

Drug behavior in undercooled melts is highly important for pharmaceutics with regard to amorphous solid dispersions, and therefore, categories were recently introduced that differentiate glass formers (GFs) from other drugs that are nonglass formers (nGFs). The present study is based on the assumption that molecular properties relevant for the so-called Prigogine-Defay (PD) ratio would be indicative of a drugs glass-forming ability. The PD ratio depends in theory on the entropy of fusion and molar volume. Experimental data were gathered from a broad set of pharmaceutical compounds (n = 54) using differential scanning calorimetry. The obtained entropy of fusion and molar volume were indeed found to significantly discriminate GFs from nGFs. In a next step, the entropy of fusion was predicted by different in silico methods. A first group contribution method provided rather unreliable estimates for the entropy of fusion, while an alternative in silico approach seemed more promising for drug categorization. Thus, a significant discrimination model employed molar volume, a so-called effective hydrogen bond number, and effective number of torsional bonds (or torsional units) to categorize GFs and nGFs (p ≤ 0.0000). The results led to new insights into drug vitrification and to practical rules of thumb. The latter may serve as guidance in pharmaceutical profiling and early formulation development with respect to amorphous drug formulations.

Glass-forming ability of compounds in marketed amorphous drug products.

Graphical abstract Figure. No caption available. Abstract This note is about the glass‐forming ability (GFA) of drugs marketed as amorphous solid dispersions or as pure amorphous compounds. A thermoanalytical method was complemented with an in silico study, which made use of molecular properties that were identified earlier as being relevant for GFA. Thus, molar volume together with effective numbers of torsional bonds and hydrogen bonding were used to map drugs that are as amorphous products on the market either as solid dispersion of without co‐processed carrier as amorphous drug in a solid dosage form. Differential scanning calorimetry experiments showed that most compounds were stable glass formers (GFs) (class III) followed by so‐called unstable GFs (class II) and finally, only vemurafenib was found in class I with increased crystallization propensity. The in silico results, however showed that all drugs were either clearly in the chemical space expected for GFs or they were borderline to the region that holds for high crystallization tendency. Interestingly, the pure amorphous compounds scattered in a very confined region of the molecular predictors. These findings can guide amorphous product development of future drug candidates. Based on the compound location in the given chemical space, amorphous formulation opportunities can be balanced against the risks of physical instability upon storage.

A Systematic Study of Molecular Interactions of Anionic Drugs with a Dimethylaminoethyl Methacrylate Copolymer Regarding Solubility Enhancement

The methacrylate-copolymer Eudragit EPO (EPO) has raised interest in solubility enhancement of anionic drugs. Effects on aqueous drug solubility at rather low polymer concentrations are barely known despite their importance upon dissolution and dilution of oral dosage forms. We provide evidence for substantial enhancement (factor 4-230) of aqueous solubility of poorly water-soluble anionic drugs induced by low (0.1-5% (w/w)) concentration of EPO for a panel of seven acidic crystalline drugs. Diffusion data (determined by 1H nuclear magnetic resonance spectroscopy) indicate that the solubility increasing effect monitored by quantitative ultraperformance liquid chromatography was caused primarily by molecular API polymer interactions in the bulk liquid phase. Residual solid API remained unaltered as tested by X-ray powder diffraction. The solubility enhancement (SE) revealed a significant rank correlation (rSpearman = -0.83) with rDiffAPI, where SE and rDiffAPI are defined ratios of solubility and diffusion coefficient in the presence and absence of EPO. SE decreased in the order of indomethacin, mefenamic acid, warfarin, piroxicam, furosemide, bezafibrate, and tolbutamide. The solubilizing effect was attributed to both ionic and hydrophobic interactions between drugs and EPO. The excellent solubilizing properties of EPO are highly promising for pharmaceutical development, and the data set provides first steps toward an understanding of drug-excipient interaction mechanisms.

Unexpected Solubility Enhancement of Drug Bases in the Presence of a Dimethylaminoethyl Methacrylate Copolymer

The methacrylate copolymer Eudragit EPO (EPO) has previously shown to greatly enhance solubilization of acidic drugs via ionic interactions and by multiple hydrophobic contacts with polymeric side chains. The latter type of interaction could also play a role for solubilization of other compounds than acids. The aim of this study was therefore to investigate the solubility of six poorly soluble bases in presence and absence of EPO by quantitative ultrapressure liquid chromatography with concomitant X-ray powder diffraction analysis of the solid state. For a better mechanistic understanding, spectra and diffusion data were obtained by 1H nuclear magnetic resonance (NMR) spectroscopy. Unexpected high solubility enhancement (up to 360-fold) was evidenced in the presence of EPO despite the fact that bases and polymer were both carrying positive charges. This exceptional and unexpected solubilization was not due to a change in the crystalline solid state. NMR spectra and measured diffusion coefficients indicated both strong drug-polymer interactions in the bulk solution, and diffusion data suggested conformational changes of the polymer in solution. Such conformational changes may have increased the accessibility and extent of hydrophobic contacts thereby leading to increased overall molecular interactions. These initially surprising solubilization results demonstrate that excipient selection should not be based solely on simple considerations of, for example, opposite charges of drug and excipient, but it requires a more refined molecular view. Different solution NMR techniques are especially promising tools to gain such mechanistic insights.

The quest for exceptional drug solubilization in diluted surfactant solutions and consideration of residual solid state

ABSTRACT Solubility screening in different surfactant solutions is an important part of pharmaceutical profiling. A particular interest is in low surfactant concentrations that mimic the dilution of an oral dosage form. Despite of intensive previous research on solubilization in micelles, there is only limited data available at low surfactant concentrations and generally missing is a physical state analysis of the residual solid. The present work therefore studied 13 model drugs in 6 different oral surfactant solutions (0.5%, w/w) by concomitant X‐ray diffraction (XRPD) analysis to consider effects on solvent‐mediated phase transformations. A particular aspect was potential occurrence of exceptionally high drug solubilization. As a result, general solubilization correlations were observed especially between surfactants that share chemical similarity. Exceptional solubility enhancement of several hundred‐fold was evidenced in case of sodium dodecyl sulfate solutions with dipyridamole and progesterone. Furthermore, carbamazepine and testosterone showed surfactant‐type dependent hydrate formation. The present results are of practical relevance for an optimization of surfactant screenings in preformulation and early development and provide a basis for mechanistic modeling of surfactant effects on solubilization and solid state modifications. Graphical abstract Figure. No Caption available.

Miniaturized Screening Tools for Polymer and Process Evaluation

There has been an increasing interest in studying amorphous solid dispersion (ASD) approaches in response to the increasing number of poorly soluble compounds from pharmaceutical discovery in recent years. Although ASD has demonstrated drastic bioavailability enhancement, concerns over the physical instability remain as valid. By engineering amorphous solid dispersion with an appropriate polymer, the physical stability of ASD can be improved significantly. The identification of appropriate polymer and drug loading for ASD development, however, has been based on “trial and error” and is time consuming. High-throughput miniaturized screening systems offer attractive opportunities for the development of ASD by streamlining the polymer and drug loading selection processes with low demand on material, time, and resources. The main focus of this chapter is to describe and review the current miniaturized experimental ASD screening methods, including solvent casting, solvent shift, coprecipitation, melt fusion, freeze drying, and spin coating. The criticality of understanding basic physicochemical properties of active pharmaceutical ingredient (API) in developing a successful ASD is discussed. The drug–polymer interaction in the solid state and in solution upon dissolution is also briefly tackled. Finally, a rational approach for polymer and drug loading selection based on the balance of biopharmaceutical performance and ASD stability is provided.