1. summary

 A solid dispersion (ASD) is the most effective strategy to improve solubility, dissolution rate and oral bioavailability. Solid dispersion can be prepared in a variety of ways, such as melting method, hot melting extrusion (HME) process, melting agglomeration, spray drying, melting, solvent evaporation, supercritical anti-solvent (SAS), electrospinning, etc. The HME technology is very suitable for preparing solid dispersion. Because it is a simple, high-throughput, durable process with a limited number of processing steps requiring no solvent or water, it can easily compact fluffy and low-mobility materials, produce minimal dust, and provide an effective continuous production process. Therefore, many pharmaceutical companies are paying more and more attention to improving the solubility and bioavailability of insoluble drugs through HME technology. As a researcher of a pharmaceutical company, when I was just involved in the preparation of solid dispersions using HME, I was not very clear about the relationship between the factors to be considered and the key quality attributes of the preparation. In general, I only investigated one factor according to experience or literature methods, and the project did not go smoothly. Therefore, by learning the ICH guidelines about quality from design (QbD) content, combining with literature and practical work cases, summarizing the general process of hot melt extrusion preparation based on QbD, and sharing cases, hoping to learn and make progress together with everyone.

The Technical Requirements for Human Use (ICH) Guidelines ICH Q8 (Product Development), ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) provide guidance for the application of quality from design (QbD). Successful implementation of the QbD requires an understanding of the target product quality profile (QTPP) and the key quality attributes (CQA) of the product; also, the relationship between the CQA and critical material attributes (CMA) and critical process parameters (CPP) should be considered. The relationship of CQA to CMA and CPP requires the accumulation of knowledge and experience, and the experimental design (DoE) method for screening and optimizing experimental parameters can be applied to the development of high-quality amorphous solid dispersion (ASD) preparations using the HME process. Therefore, we will learn the QbD process of HME based on a full understanding of the relationship between CQA and CMA and CPP.

2. QbD

QbD is a step-by-step systematic approach in drug development, starting with predetermined goals and emphasizing the bridging between product and process understanding based on rational science and quality risk management can help to establish a method of ensuring product quality. The principles and objectives of the QbD include:

① Risk assessment and root cause analysis to identify the prescribing and process factors that affect the product quality;

② Systematic experimental methods aim to improve product development and production efficiency by setting meaningful limits for key prescribing and process variables;

③ Determine the design space for prescription and process variables by increasing the understanding of product, process design and control;

④ Post-approval change management using the knowledge acquired from the design space.

 The general process of QbD development is shown in Figure 1, requiring the target product quality profile (QTPP) and CQA based on the product characteristics and purpose, and then based on experience and previous research, and establishing the relationship with CQA, and then conduct risk assessment and experimental design to determine the scope of risk, to help determine the control strategy.

Figure 1 Order and elements of the QbD paradigm in product development.

 Taking the HME preparation of ASD as an example, the elements in QbD are mainly shown in Figure 2. The QTPP, CQA, CMA, CPP and the corresponding risk assessment and experimental design in the HME will be introduced below

Figure 2. QbD elements of ASD preparation by HME.

(1) Target product quality overview: QTPP

QTPP is the basis of product development, aiming to ensure the quality of the product, the ideal QTPP should fully consider the safety and effectiveness of the product, generally including the following contents:

① Characteristics of the formulation or dosage form (e. g., type, route of administration, and specification);

② Quality attributes of the preparation (such as content determination, degradation products, water content and content uniformity);

③ Pharmacokinetic parameters and microbial attributes.

(2) Key Quality Properties (CQA)

 CQA is defined as physical, chemical, biological or microbiological properties or characteristics and shall be within appropriate limits, ranges, specification or distribution to achieve the desired product quality. CQA is a subset of QTPP, but CQA provides more mechanistic views on product and process understanding than QTPP. The CQA represents the attributes of the final formulation, and therefore, the CQA needs to be monitored during product development to ensure consistency in product performance and process durability.

 CQA can generally be determined by previous product or process experience and literature reports, and the most important CQA of ASD produced by HME include residual crystallinity, impurities, assay, dissolution and water content.

① Residual crystallinity: The residual crystallinity of the drug product reflects the amount of crystallized API in the ASD prepared by the HME. Generally, the crystallized API will reduce the dissolution and bioavailability of the preparation, so CMA and CPP should be optimized to reduce the residual crystallinity and obtain the amorphous ASD.

② Impurity: API degradation is an important CQA for ASD, especially for thermal API, as degradation characteristics may affect patient safety and effectiveness.

③ Assay: This assay is an important quality attribute because it affects the safety and effectiveness of developing ASD.

④ Dissolution: Solubility can be one of the important CQAs of ASD, because in many cases, the dissolution curve of ASD can reflect the oral bioavailability in vivo. This is because the API in ASD has a higher kinetic solubility, which exceeds the API supersaturation level, and the solubility level of ASD can simply and intuitively explain whether the prepared ASD is as expected.

⑤ Water content: The water content of the preparation can affect the physical and chemical stability of ASD, and the increase of water content of the preparation due to excessive water content or improper preservation will lead to the transformation of amorphous API to crystal form, leading to the decrease of dissolution and bioavailability.

(3) Key material attribute CMA

CMA is the nature of the drug substance and excipients with a direct impact on CQA and is considered an essential element of product quality regulation. CMA for ASD development using HME includes the rheological properties of API and polymer materials, glass conversion temperature Tg, degradation temperature Td, particle size, and powder fluidity. Polymer type (quick-release vs sustained-release and pH-dependent or pH-independent) and properties (amorphous, crystalline, or semi-crystalline) are equally important. The study and characterization of these parameters provide information for identifying the CPP of the HME.

(4) Key process parameters: CPP

 In the product development process, we can fully understand the prescription and carefully evaluate the impact of the CPP and its boundary conditions on the critical CQA, and achieve the more successful optimization of the HME process. For HME's preparation of ASD, CPP mainly includes material barrel temperature, screw speed, feed rate and screw design, etc. These factors influence each other and jointly affect the process performance and CQA of ASD.

① The cylinder temperature will mainly affect the viscosity of API and polymer. A suitable cylinder temperature should meet the miscibility requirements between API and polymer, and achieve the best melt viscosity.

② Screw speed and feed speed should be matched, and ideally should be maintained at a high level to ensure adequate material mixing while shortening the material dwell time and providing high throughput.

③ Screw design is a crucial parameter in the HME process. The screw can be roughly divided into delivery module and kneading module. The kneading module can integrate to generate strong shear force for better mixture and significantly improve the quality of cocrystal. However, too many kneading modules will also lead to a longer residence time, which will affect the production efficiency or cause the generation of impurities. Therefore, it is necessary to design a reasonable screw combination for both efficiency and quality.

(5) Risk assessment

 Linking CMA and CPP to CQA by risk assessment methods is required for qualitative risk analysis. The primary objective of the risk assessment approach is to identify, analyze and evaluate the potential risks associated with each CMA and CPP and their impact on the product CQA. The most commonly used risk assessment tools in HME-based ASD product development are the Ishikawa Fish Bone Map and Failure Mode Effects Analysis (FMEA).

Figure 3 Fish bone plot highlights all possible content variables and the potential risks of CMA and CPP to drug product CQA.

Figure 3 Fish bone maps related to the development of the ASDs

The FMEA can be used to evaluate the mode, cause and impact of each potential failure, its severity (S), incidence (O) and detectability (D) of each potential failure; these parameters are usually expressed in a 1-10 scale. Each failure is rated on three-level scales, namely high (H), medium (M), or low (L). Based on the experience of literature, prescribing and process knowledge, the association of CMA or CPP based on HME preparation with CQA and their impact on CQA are shown in Table 1 and Table 2.

Table 1 Effect of CMA on CQA

Table 2 Effects of CPP on CQA

(6) Experimental design of the DoE

 Once risk factors for CMA and CPP have been identified, the next step is to perform DoE, screen and optimize CMA and CPP to reduce the risks associated with CMA and CPP, ultimately establishing design space during formulation development.

 The DoE design is divided into screening and optimized design, and the purpose of the screening design is to determine the key factors and their levels. In contrast, the optimized design is mainly used to identify factors with optimal levels to achieve an optimal response. In the early development stage, many parameters can affect the nature and performance of ASD. Therefore, first determining the actual impact of CQA and screening its levels using a screening design reduces potential risks in the product / process development process.

Process optimization of ASD produced through HME technology requires knowledge of CQA, CMA, CPP, risk assessment tools, and experimental design. The knowledge gained from these QbD elements helps to ensure the consistency of product quality. Choosing and implementing the appropriate experimental design (DoE) approach to screen and optimize prescribing and process variables remains a significant challenge. The following will be learned by two specific examples in the literature.

3. Specific example

Amit Gupta And others developed the extrusion hydrochloride with the custom sieve design software. The author designed two sets of experiments. The first group of experiments studied the influence of polymer type and plasticizer level on extrusion processing quality; the second set of experiments and determined the influence of process parameters (such as screw speed and material barrel temperature) on the extrusion appearance, torque, disintegration time and dissolution curve. The experimental design is shown in Table 3. Experimental design 1 includes two input variables, one classification (polymer type) and one continuous (plasticizer level) factor; the experiment design 2 includes three factors-one classification factor (polymer type) and two continuous factors (screw speed and barrel temperature); the response (dependent variable) variables of two experiments are extruder appearance, machine torque and disintegration time and dissolution.

Table 3: DoE for prescription and process screening

1, and the experimental design of 1

Experimental design 1 is to study the influence of the composition of the extrusion quality, designed the influence of different polymer types (VA64, HPMC, Eudragit EPO, Affinisol 15LV) and plasticizer level on the product appearance, torque and disintegration time, is to select suitable polymer to make better miscibility with drugs, and prepare easy to HME treatment and minimum loss of drug content solid dispersion. The results are shown in Table Table 4.

 Table 4 Experimental Design 1 Results

Extrusion more transparency and motor torque, Affinisol 15LV and Kollidon VA64 is more suitable as PZB drug matrix, because their extrusion torque is lower, extrusion more transparent, reflects the two polymers and API have better mixing ability, and viscosity is suitable, more suitable for processing, so the effect of plasticizer viscosity has little effect on them.

 Polymer type has a strong effect on the disintegration time limit of drug extrudates, the longest in aqueous medium in Eudragit EPO polymer, followed by Kollidon VA64 and HPMC, and Affinisol 15LV polymer with the shortest in DT.

From the experiment in experimental design 1, the optimal polymer types are Kollidon VA64 and Affinisol 15LV.

2, and the experimental design of 2

Based on the optimization study results of polymer type selection, Kollidon VA64 and Affinisol 15LV were selected for further process optimization studies. The system DoE design consists of three factors: —— one classification factor (polymer type) and two continuous factors (screw speed and stock barrel temperature). Factors and responses are summarized in Table 5 below.

 Table 5 Experimental Design 2 Results

According to the results, the Kollidon VA64 extrusion prepared at low screw speed and low barrel temperature led to less transparency (HME-13 test), increasing the screw speed led to extrusion transparency (HME-15 test), and high temperature combined with low or high screw speed led to complete dissolution of the PZB-drug in its matrix and observed transparent extrusion (test HME-14 and HME-16). So it can be concluded that higher speed and barrel temperature contribute to the preparation of solid dispersion. In addition, in order to investigate the influence of various factors on dissolution, the authors concluded that the significant order of dissolution response was polymer type> screw speed> material barrel temperature. In other words, ASD dissolution is most affected by the polymer type, and in order to obtain the target dissolution, the polymer type should be determined first, and then the screw speed and the barrel temperature should be screened to obtain high quality ASD.

Ultimately, the authors concluded that extrusions prepared using a 1:2 drug-polymer ratio (Affinisol 15 LV) had better in vitro dissolution and a minimum disintegration time limit. In addition, the bioavailability (AUC) of PZB-extrusion (test formulation A) using Affinisol polymers was 4.79 and 1.66 times higher respectively compared with free PZB) hydrochloride and commercially available products (Votrient® tablets).

4. sum up

Due to its robust handling, improved product stability, and advanced control strategy, HME is a mature technology for the development of ASD. A mechanistic understanding of the QbD elements provides insights related to key prescribing and process variables. Screening and optimization of product and process parameters using DoE methods is critical in ASD development. Correct identification and understanding of the CQA, CMA and CPP of ASD and the relationship between these QbD elements will help us to identify the major formulation and process parameters that may affect ASD performance. To help us to correctly use the DOE model, reasonably and efficiently select the prescription process, and help to enlarge, and promote the smooth progress of the project.

reference documentation:

[1]Patil, Hemlata, et al."Hot-melt extrusion: from theory to application in pharmaceutical formulation—where are we now?."AAPS PharmSciTech 25.2 (2024): 37.

[2]Gupta, Amit, et al."QbD-Based Development and Evaluation of Pazopanib Hydrochloride Extrudates Prepared by Hot-Melt Extrusion Technique: In Vitro and In Vivo Evaluation."Pharmaceutics 16.6 (2024): 764.

[3]Repka M A , Butreddy A , Bandari S .Quality-by-design in hot melt extrusion based amorphous solid dispersions: An industrial perspective on product development[J].European Journal of Pharmaceutical Sciences, 2020, 158.DOI:10.1016/j.ejps.2020.105655.

[4] Li Mengting, Liu Qing, Zhang Yaqi, Ye Mengdie, Wang Wenxi. Preparation and performance investigation of the ternary supersaturated solid dispersion system based on the QbD concept [J]. Chinese Journal of Pharmacy, 2020,55 (17): 1450-1455.

 

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