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Application of PAT-based feedback control for the crystallization of pharmaceuticals in porous media David A Acevedo, Jing Ling, Keith Chadwick, and Zoltan K Nagy Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00303 • Publication Date (Web): 11 Jul 2016 Downloaded from http://pubs.acs.org on July 13, 2016
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Application of PAT-based feedback control for the crystallization of pharmaceuticals in porous media David A. Acevedoa, Jing Lingb, Keith Chadwickb, Zoltak K. Nagya,* a
School of Chemical Engineering, bDepartment of Industrial and Physical Pharmacy, Purdue University, West Lafayette, 47907, IN
Abstract
The purpose of this work is to implement a feedback control approach during the cooling crystallization of paracetamol (PCM) in porous media. The main objective is to increase the amount of PCM in the alginate beads (i.e. drug loading) and minimizing the heterogeneous nucleation occurring in the bulk system. Two types of cooling profiles were considered: fast linear and programmed cooling. In addition, the model-free Direct Nucleation Control (DNC) strategy was evaluated and compared to controlled cooling crystallization scenarios. A mean drug loading from 49 to 69 % was achieved through the various scenarios. The application of DNC increased or maintained the mean drug loading achieved compared to the cooling only scenarios, while a decrease of about 75 % was observed in the batch-to-batch variability. The paper demonstrates the benefits of using feedback control approaches to increase drug loading, decrease batch-to-batch variability and control dissolution behavior of drug-loaded polymer microspheres.
Corresponding author: Zoltan K. Nagy Address: Forney Hall of Chemical Engineering, 1060 480 Stadium Mall Drive West Lafayette, IN 47907-2100 Phone: (765) 494-0734 Email:
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Web address: https://engineering.purdue.edu/ChE/People/ptProfile?id=79574 Application of PAT-based feedback control for the crystallization of pharmaceuticals in porous media David A. Acevedoa, Jing Lingb, Keith Chadwickb, Zoltak K. Nagya,* a
School of Chemical Engineering, bDepartment of Industrial and Physical Pharmacy, Purdue University, West Lafayette, 47907, IN.
[email protected] Abstract
The purpose of this work is to implement a feedback control approach during the cooling crystallization of paracetamol (PCM) in porous media. The main objective is to increase the drug loading (DL) in the alginate beads and minimizing the heterogeneous nucleation occurring in the bulk system. Two types of controlled cooling profiles and the model-free Direct Nucleation Control (DNC) strategy were evaluated. A mean DL from 49 to 69 % was achieved through the various scenarios. The application of DNC increased or maintained the mean DL achieved compared to the cooling only scenarios, while a decrease of about 75 % was observed in the batch-to-batch variability. SEM images showed that crystals of different crystal size distribution (CSD) were obtained for the various cooling scenarios, which can be related to the different operating trajectories in the phase diagram achieved during the feedback control approaches. The possibility of manipulating the CSD of particles within the polymer beads can be used to tailor dissolution profile and bioavailability. The paper demonstrates the benefits of using feedback control approaches to increase DL, decrease batch-to-batch variability and control dissolution behavior of drug-loaded polymer microspheres. Keywords: Process Analytical Technology, porous media, alginate, Direct Nucleation Control, crystallization
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1. Introduction
Pharmaceutical products have been commonly produced using batch operation due to the flexibility offered for processes of many simple steps with changing recipes.1 However, batch-tobatch variability creates a major disadvantage due to the high economic penalty of producing offspec products. The Food and Drug Administration (FDA) released guidelines for current good manufacturing practices (CGMP) for the twenty-first century and quality by design (QbD) initiatives to improve the manufacturing and quality of pharmaceutical products throughout the development and implementation of new and efficient technologies.2,3 As part of the initiative, new product design approaches to enhance the efficacy of the pharmaceutical product have shown increased interest. The development of new drug delivery methods to tailor the desired drug release have been of major interest throughout the past decades; some of the drug delivery methods are based on substrates, polymer films and microspheres. 4-7
The use of degradable polymer microspheres for drug delivery is advantageous because microspheres can be ingested or injected.7-14 Moreover, the microspheres can be tailored for desired release profiles and organ-targeted release. The drug release can be affected by various attributes of the polymer properties such as molecular weight, size and size distribution, porosity, morphology and make-up. Drug release is a complex process, which has been shown to follow two main expulsion courses: high initial burst due to medication at the sphere surface and a more uniform release stage that depends on diffusion and degradation.8 Microspheres can be prepared by polymerization of monomers or linear polymers through various techniques such as emulsion, dispersion, suspension, and sedimentation polymerization. The maximum amount of drug
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loading (DL) achieved so far throughout the common techniques used to produce polymer microspheres for drug delivery is around 20-50%.7,9
Recent work showed the use of alginate microgel particles as encapsulating vehicles for hydrophilic and hydrophobic drugs.11 The maximum DL of acetaminophen obtained by varying only the alginate bead properties was close to 30%; however, no further study was performed on how the crystallization step can influence DL. The main focus of previous work has been the optimization of the polymer particles for achieving different release profiles.12 Attempts to study and optimize the crystallization step in microspheres has been performed in previous work.14 However, the various crystallization steps can be monitored and controlled to achieve better product quality using suitable process analytical technologies (PAT) and new feedback control approaches.3,15,16 PAT-based feedback control technologies can enhance the economic performance of the crystallization process, increase controllability of the physical properties of the product, and minimize batch-to-batch variability.17
One of the main challenges in crystallization process development is to develop and implement control strategies to achieve a desired size and shape of the final product.20-22 A continuous crystallization process was proposed by Griffin et al. that can produce APIs with a small mean size and narrow distribution using a product classifier configuration where large crystals were dissolved and recycled.24 Nagy et al. presented a methodology for the dynamic optimization of the crystal size distribution (CSD) considering growth, nucleation, and dissolution mechanism for batch cooling crystallization processes.25 The same group also proposed a model-free control approach, the direct nucleation control (DNC), in which the total number of crystals is controlled by implementing automated dissolution cycles.26 It has been
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shown that controlled dissolution steps during the crystallization process reduce crystal fines and can positively impact the achievable mean size and size distribution of the product. This was also demonstrated for a continuous single stage crystallization process in which a dissolver vessel was used to control fines.27
The purpose of this work is to evaluate the benefits of controlling the bulk crystallization in the presence of alginate porous particles. The DNC approach was implemented as an inferential control strategy to evaluate its impact on the final product quality. The main goal of the control approach was to minimize bulk nucleation, and maximize DL of the alginate porous particles with reduced variability. The experimental results indicate that the application of a suitable feedback control strategy in the crystallization step during the encapsulation of active pharmaceutical ingredients in a porous media can be beneficial to improve final product quality such as achieving increased drug loading with lower batch-to-batch variability and can also serve as a methodology to tailor the crystal size distribution in the porous system, influencing thereby the in vivo or in vitro dissolution behavior of the particles. The implementation of a suitable feedback control approaches is also required for the application of process intensification concepts enabled by the possibilities to conduct controlled crystallization within porous microspheres. Figure 1 illustrates how the controlled crystallization within porous substrate based technology can provide a more efficient, intensified pharmaceutical manufacturing process that significantly reduces the number of unit operations typically required in solid dosage manufacturing. The drug loaded polymer particles can be compressed into tablets or encapsulated. The addition of lubricant could be necessary for efficient tableting. However, the properties of the polymer particles can be tailored to improve the compressibility and compactability during the tableting process. 5 ACS Paragon Plus Environment
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Figure 1. General and proposed pharmaceutical manufacturing platform using API crystallization within porous polymer microspheres.
2. Materials and methods 2.1. Materials
4-Acetaminophenol (paracetamol, PCM, Alfa Aesar) with a purity of 98.0% in mass fraction was used in the various cooling crystallization experiments. The solubility of paracetamol in ethanol was obtained from literature.28 Sodium alginate, sodium bicarbonate, acetic acid and calcium chloride were used for the preparation of the porous microspheres. A homogenized solution of 2% w/w sodium alginate, 0.5% w/w sodium bicarbonate in deionized water was added to a 2% w/w of calcium chloride solution using a pipette. The calcium chloride solution contained 0.3% w/w of acetic acid which serves as cross-linking agent. The droplets were put under vacuum (
