Influence of mechanical and thermal energy on nifedipine amorphous solid dispersions prepared by hot melt extrusion: Preparation and physical stability

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Abstract

Hot melt extrusion (HME) has been used to prepare solid dispersions, especially molecularly dispersed amorphous solid dispersions (ASDs) for solubility enhancement purposes. The energy generated by the extruder in the form of mechanical and thermal output enables the dispersion and dissolution of crystalline drugs in polymeric carriers. However, the impact of this thermal and mechanical energy on ASD systems remains unclear. We selected a model ASD system containing nifedipine (NIF) and polyvinylpyrrolidone vinyl acetate (PVP/VA 64) to investigate how different types of energy input affect the preparation and physical stability of ASDs. Formulations were prepared using a Leistritz Nano-16 extruder, and we varied the screw design, barrel temperature, screw speed, and feed rate to control the mechanical and thermal energy input. Specific mechanical energy (SME) was calculated to quantitate the mechanical energy input, and the thermal energy was estimated using barrel temperature. We find that both mechanical and thermal energy inputs affect the conversion of crystalline NIF into an amorphous form, and they also affect the level of mixing and the degree of homogeneity in NIF ASDs. However, for small size extruders (e.g., Leistritz Nano-16), thermal energy is more efficient than mechanical energy in preparing NIF ASDs that have better stability.

Graphical abstract

Material contributions (viscosity and miscibility) and extrusion process contributions (heat transfer and mechanical energy) to the design space of nifedipine and Kollidon® VA 64 amorphous solid dispersions.

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Introduction

Applications of high-throughput screening in drug discovery have improved efficiency and generated a large number of drugs that are potentially therapeutically active, have high molecular weight, and have preferable permeability across biomembranes. However, most of these drugs exhibit poor solubility in aqueous solutions (Hauss, 2007, Keserü and Makara, 2009). Prior research has reported the strategy of using amorphous solid dispersions (ASDs) to deliver and improve the bioavailability of poorly water-soluble drugs (He and Ho, 2015, Vasconcelos et al., 2016). The conversion of crystalline drugs to their amorphous form results in high drug chemical potential and improved solubility, dissolution, and bioavailability of ASD systems compared to the crystalline form (Alonzo et al., 2010, Huang et al., 2016a, Jang et al., 2013). Despite the success of using ASDs, their physical stability problems often impede their application (Huang and Dai, 2014, Vasconcelos et al., 2007). Hence, it is necessary to study the factors that can impact ASD physical stability.

Hot-melt extrusion (HME) is a continuous manufacturing process that has been adapted for various applications in drug design and development, such as shaping devices, taste masking, and the preparation of modified release and solid dispersion formulations (Crowley et al., 2007, Lakshman et al., 2008). Ideally, HME is employed to prepare molecularly dispersed ASDs, which require that the process provides enough energy to convert the drug from its crystalline to its amorphous form and sufficiently mix the drug and the polymer carrier (Boersen et al., 2015). The energy input from the extruder consists of thermal energy, which is generated by heat conduction from the barrel and screw elements; and mechanical energy, which is generated by the extruder motor and screw elements. The type and degree of energy input lead to different levels of mixing between the drug and the polymer, and both thermal and mechanical energy inputs have significant impact on preparing ASD systems (Hanada et al., 2018, Yang et al., 2016).

Previous studies investigate the influence of different extrusion processing parameters (e.g., temperature, screw speed, screw elements, feeding rate) on the physical properties of an ASD (Lakshman et al., 2008, Lang et al., 2014, Qian et al., 2010). Yang et al. investigate the effects of thermal energy on the preparation of NIF ASDs and the drug’s miscibility (Yang et al., 2016). They report that, above a critical temperature, the extrusion process achieved NIF ASDs at a molecular level. In addition, Hanada et al. demonstrate that higher mechanical energy input can improve the miscibility of indomethacin (IND) in ASDs, subsequently improving its dissolution and stability (Hanada et al., 2018).

However, these two studies emphasize the effects of one type of energy input, either thermal energy (barrel temperature) or mechanical energy (specific mechanical energy), on the properties of ASDs. The relationship between the mechanical and thermal energies, and their effects on the preparation and physical stability of ASDs, still remains unclear. Moreover, different energy inputs may influence the stability of an ASD through different mechanisms, including reduction in drug mobility, drug–polymer interaction, water sorption, and thermodynamic properties of the ASD (e.g., enthalpy, entropy, heat capacity, chemical potential) (Prodduturi et al., 2007, Sarode et al., 2013).

Therefore, in this paper, we aim to investigate how mechanical and thermal energy inputs relate to the preparation and physical stability of NIF ASDs. Also, by understanding the effects of processing factors, we aim to define a design space through quality by design for NIF and PVP/VA 64 systems. Due to the larger surface-to-volume ratio of smaller extruders (e.g., a Leistritz 16 mm extruder), their heat transfer is more efficient and significant than larger extruders (Huang et al., 2017). Thus, we hypothesize that thermal energy has the dominant effect on the preparation and physical properties of the ASDs using a Leistritz 16 mm extruder. Also, we hypothesize that higher energy input leads to more homogeneous ASDs.

Nifedipine (NIF) was chosen as the model drug (Fig. 1), and Kollidon® VA 64 (average molecular weight = 45,000–70,000) was chosen as the model polymer (Fig. 1) to study the impact of mechanical and thermal energy inputs on the preparation and physical stability of NIF–PVP/VA 64 ASDs. The mechanical energy was calculated based on the processing conditions. The thermal energy was qualitatively estimated using the barrel temperature.

Section snippets

Materials

Crystalline NIF of Modification Ⅰ was purchased from Letco Medical (Decatur, AL) (Grooff et al., 2007). Kollidon® VA 64 (PVP/VA64), Kollidon® 12 PF (PVP K12), Kollidon® 25 (PVP K25), and Kollidon® 90F (PVPK90) were donated by the BASF Corporation (Florham Park, NJ). Shin-Etsu AQOAT® AS LMP (HPMC AS LMP) was donated by Shin-Etsu Chemical Co. Ltd., (Tokyo, Japan). Nile red was obtained from Acros Organics (Geel, Belgium). HPLC–grade acetonitrile and water were purchased from Fisher Scientific Co.

Flory–Huggins modeling

The Gibbs free energy of mixing was used to construct a diagram with the substitution of the value of the interaction parameter, χ, into Eq. (1) at various temperatures, as shown in Fig. 2A. The free energy of mixing between NIF and PVP/VA 64 was negative across the entire temperature range (25–200 °C), which indicates that homogeneous mixtures of NIF and PVP/VA 64 are thermodynamically favorable for all compositions within this temperature range. For NIF–PVP K12, K25, and K90 systems at room

Study design

NIF is a Biopharmaceutics Class Ⅱ (BCS II) drug, which has poor water solubility but high permeability in the human body. Amorphous NIF can be achieved by the melt-quench method. During the reheating process, amorphous NIF has a tendency to recrystallize due to its relatively rigid structure (Baird et al., 2010). Due to its intermediate crystallization tendency, the crystallization of NIF in ASDs under stressed conditions (i.e., elevated temperature and humidity) has been observed (Marsac et

Conclusions

In this study, we investigate the influences of mechanical and thermal energy on the preparation and physical stability of NIF–PVP/VA 64 ASDs. We demonstrate that small extruders (Leistritz Nano-16) generate thermal energy that is more effective in the amorphization of NIF in PVP VA64. We also show that small extruders exhibit thermal energy input that has more impact on achieving a homogeneous ASD system, which results in better physical stability. Last, based on quality by design, we define a

Acknowledgement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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    This work was presented in part as a poster at the American Association of Pharmaceutical Scientists Annual Meeting: PharmSci360, November 2018, Washington, DC.

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