Polymer-inducing chemical degradation of amorphous solid dispersions driven by drug-polymer interactions for physical stabilization.

Intermolecular interactions between active pharmaceutical ingredients (APIs) and carrier polymers are important for the long-term physical stability of amorphous solid dispersions (ASDs). However, the negative impact of intermolecular interactions on chemical stability has rarely been reported. In this study, the relationship between intermolecular interactions and physical and chemical stability was investigated using two ASDs composed of API and hydroxypropyl methylcellulose acetate succinate (HPMCAS) with different stabilities: ASD1 was physically stable but chemically unstable, whereas ASD2 was physically unstable but chemically stable. Ionic-bonding between the pyridine nitrogen in the API and succinyl group in HPMCAS was found in both ASDs. The additional interaction between the succinyl group in HPMCAS and the hydroxyl group in the API was suggested only in ASD1. It was concluded that the additional interaction contributed to the physical stability of ASD1; however, it accelerated the chemical reaction between the succinyl and hydroxyl groups to generate succinyl ester owing to its close proximity. This study shows that the intermolecular interaction between the API and carrier polymer is not always beneficial for chemical stability. Understanding the molecular states of APIs and polymers in ASDs is important for their successful development.

Compatibility and stability studies involving polymers used in fused deposition modeling 3D printing of medicines.

One of the challenges in developing three-dimensional printed medicines is related to their stability due to the manufacturing conditions involving high temperatures. This work proposed a new protocol for preformulation studies simulating thermal processing and aging of the printed medicines, tested regarding their morphology and thermal, crystallographic, and spectroscopic profiles. Generally, despite the strong drug-polymer interactions observed, the chemical stability of the model drugs was preserved under such conditions. In fact, in the metoprolol and Soluplus® composition, the drug's solubilization in the polymer produced a delay in the drug decomposition, suggesting a protective effect of the matrix. Paracetamol and polyvinyl alcohol mixture, in turn, showed unmistakable signs of thermal instability and chemical decomposition, in addition to physical changes. In the presented context, establishing protocols that simulate processing and storage conditions may be decisive for obtaining stable pharmaceutical dosage forms using three-dimensional printing technology.

Factors Controlling Drug Release in Cross-linked Poly(valerolactone) Based Matrices.

There is keen interest in the development of biocompatible and biodegradable implantable delivery systems (IDDS) that provide sustained drug release for prolonged periods in humans. These systems have the potential to enhance therapeutic outcomes, reduce systemic toxicity, and improve patient compliance. Herein, we report the preparation and physicochemical characterization of cross-linked polymeric matrices from poly(valerolactone)- co-poly(allyl-δ-valerolactone) (PVL- co-PAVL) copolymers for use in drug delivery. A series of well-defined PVL- co-PAVL copolymers (PDI < 1.5) that vary in terms of MW and AVL content were prepared by ring opening polymerization catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene. A subsequent cross-linking reaction using 1,6-hexanedithiol led to solid cylindrical amorphous or semicrystalline matrices as potential IDDS. High loading levels (up to 20% (w/w)) of several model drugs that vary in physicochemical properties, including paclitaxel, triamcinolone acetonide and hexacetonide, curcumin, and acetaminophen, were achieved using a postloading method in organic solvent. Drug-IDDS interactions were evaluated via the group contribution method and X-ray diffraction as well as calorimetric, spectroscopic, and microscopic techniques. Results indicate superior drug-matrix compatibility for drugs bearing phenyl groups. In vitro release studies under distinct sink conditions highlight the key factors (i.e., state and loading level of drug, solubility of drug in external media, and composition of release media) that impact drug release.

Investigation of Drug-Polymer Compatibility Using Chemometric-Assisted UV-Spectrophotometry.

A simple chemometric-assisted UV-spectrophotometric method was used to study the compatibility of clindamycin hydrochloride (HC1) with two commonly used natural controlled-release polymers, alginate (Ag) and chitosan (Ch). Standard mixtures containing 1:1, 1:2, and 1:0.5 w/w drug-polymer ratios were prepared and UV scanned. A calibration model was developed with partial least square (PLS) regression analysis for each polymer separately. Then, test mixtures containing 1:1 w/w drug-polymer ratios with different sets of drug concentrations were prepared. These were UV scanned initially and after three and seven days of storage at 25 °C. Using the calibration model, the drug recovery percent was estimated and a decrease in concentration of 10% or more from initial concentration was considered to indicate instability. PLS models with PC3 (for Ag) and PC2 (for Ch) showed a good correlation between actual and found values with root mean square error of cross validation (RMSECV) of 0.00284 and 0.01228, and calibration coefficient (R²) values of 0.996 and 0.942, respectively. The average drug recovery percent after three and seven days was 98.1 ± 2.9 and 95.4 ± 4.0 (for Ag), and 97.3 ± 2.1 and 91.4 ± 3.8 (for Ch), which suggests more drug compatibility with an Ag than a Ch polymer. Conventional techniques including DSC, XRD, FTIR, and in vitro minimum inhibitory concentration (MIC) for (1:1) drug-polymer mixtures were also performed to confirm clindamycin compatibility with Ag and Ch polymers.

Exploring the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading.

The objective of this paper is to explore the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading, and elucidate whether drug-polymer compatibility, as predicted by Hansen solubility parameters (HSPs), can be used as a tool for drug-polymer pairs screening and guide the design of grafted polymeric micelles. HSPs of 27 drugs and three grafted copolymers were calculated according to group contribution method. The drug-polymer compatibilities were evaluated using the approaches of Flory-Huggins interaction parameters (χFH) and polarity difference (△Xp). Two models, model A and B, were put forward for drug-polymer compatibility prediction. In model A, hydrophilic/hydrophobic part as a whole was regarded as one segment. And, in model B, hydrophilic and hydrophobic segments were evaluated individually. First of all, using chitosan (CS)-grafted-glyceryl monooeate (GMO) based micelle as an example, the suitability of model A and model B for predicating drug-polymer compatibility was evaluated theoretically. Thereafter, corresponding experiments were carried out to check the validity of the theoretical prediction. It was demonstrated that Model B, which evaluates drug compatibility with both hydrophilic and hydrophobic segments of the copolymer, is more reliable for drug-polymer compatibility prediction. Moreover, the approach of model B allows for the selection of a defined grafted polymer with for a specific drug and vice versa. Thus, drug compatibility evaluation via HSPs with both hydrophilic and hydrophobic segments is a suitable tool for the rational design of grafted polymeric micelles. The molecular dynamics (MD) simulation study provided further support to the established model and experimental results.

Cationic amphiphilic drugs self-assemble to the core-shell interface of PEGylated phospholipid micelles and stabilize micellar structure.

Since polymeric micelles are promising and have potential in drug delivery systems, people have become more interested in studying the compatibility of polymeric carriers and drugs, which might help them to simplify the preparation method and increase the micellar stability. In this article, we report that cationic amphiphilic drugs can be easily encapsulated into PEGylated phospholipid (PEG-PE) micelles by self-assembly method and that they show high encapsulation efficiency, controllable drug release and better micellar stability than empty micelles. The representative drugs are doxorubicin and vinorelbine. However, gemcitabine and topotecan are not suitable for PEG-PE micelles due to lack of positive charge or hydrophobicity. Using a series of experiments and molecular modelling, we figured out the assembly mechanism, structure and stability of drug-loaded micelles, and the location of drugs in micelles. Integrating the above information, we explain the effect of the predominant force between drugs and polymers on the assembly mechanism and drug release behaviour. Furthermore, we discuss the importance of pKa and to evaluate the compatibility of drugs with PEG-PE in self-assembly preparation method. In summary, this work provides a scientific understanding for the reasonable designing of PEG-PE micelle-based drug encapsulation and might enlighten the future study on drug-polymer compatibility for other polymeric micelles.