A Review on the Purification of Active Pharmaceutical Ingredients
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NTU School of Chemical and Biomolecular Engineering CH2140 Chemical Engineering Unit Operations – Term Paper A Review on the Purification of Active Pharmaceutical Ingredients Executive Summary Recently the cost of health care has been growing exponentially and this is partially fuelled by the increasing price of prescription drugs. The purification of active pharmaceutical ingredients represent a significant portion of the costs of producing prescription drugs; hence, there has been a large amount of research to find more efficient purification techniques. This review paper summarizes some of the most common separation techniques and some promising techniques that are in development. It was concluded that there is no single best separation technique and that a combination of techniques is usually adopted in the API manufacturing process. The state-of-the-art techniques explored in this paper were found to address the issues of low selectivity and high solvent requirement faced in traditional separation methods. However, more research is needed to establish the feasibility of these solutions. manufacturing to ensure sustainable access to 1. Introduction prescription drugs will be paramount. Since its inception, modern medicine has greatly improved the quality of life for many. Some medications such as Paracetamol, Aspirin, or Tylenol have become so integral in our lives that it is hard to imagine a life without prescription drugs. It is expected that the demand for prescription drugs will increase significantly, mainly driven by an aging global population in developing countries in the Asia-Pacific region. This is reflected in the recent growth of the pharmaceutical market. The Figure 1 Graph depicting the market size and CAGR across the period of 2015-19 [1] global pharmaceutical market recorded a compound annual growth rate (CAGR of 3.6% during the period 2015-2019 and was estimated to All pharmaceutical drugs consist of two main be worth 1057 billion USD in 2019, as shown in components: the excipient and the Active Figure 1 [1]. Furthermore, it is projected that in Pharmaceutical Ingredient (API). Excipients are 2024, the industry will be worth 1192 billion USD, chemically inactive substances that deliver the API an increase of 12.7% since 2019 [1]. As people to the target region in a person’s body while the around the world age and chronic diseases API is the actual substance with therapeutical become more prevalent, reducing the cost of effects. 1 Chemical Engineering Unit Operations – Term Paper 3. Traditional Separation Techniques This paper focuses on the manufacturing of 3.1 Liquid-liquid Extraction APIs from raw ingredients, and specifically, the Liquid-liquid extraction (LLE), also known as separation processes involved. This is because solvent extraction, is a separation technique separation processes often represent the bulk of widely used in the pharmaceutical industry. It the cost in drug manufacturing. For instance, works based on the differential solubility of two downstream processing typically contributes 50- immiscible liquid phases and is suitable for 80% to the total manufacturing cost of separating heat-sensitive compounds. Examples therapeutical antibodies [2]. of LLE in industrial processes are the isolation of antibiotics, amino acids, and enzymes as well as The objective of this paper is to evaluate the the extraction of bioactive compounds from plant current separation process techniques and material [3]. additionally explore potential techniques that are currently in development. This paper will allow The extent of LLE is governed by subjective comparisons of the different techniques thermodynamics and can be quantified using the and facilitate the decision-making process when concept of partition coefficient, which is defined choosing the most suitable technique to be utilized as: in industry. 퐾 = 퐶1/퐶2 2. History In the early 19th century, chemists started to Where, extract and concentrate plant-based drugs such 퐾 is the partition coefficient, as morphine and quinine. In 1897, a German 퐶1 is the concentration of the solute in phase 1, chemist named Felix Hoffmann first synthesized 퐶2 is the concentration of the solute in phase 2. aspirin, a drug commonly used nowadays to treat fever. Following this discovery was the advent of Graphically, this is often represented in the form other drugs such as antibiotics, vaccines, depicted in Figure 2. The partition coefficient is a antivirals, and other synthetic drugs. As the function of parameters such as temperature and demand for synthetic drugs grew, the need for pH. The property of the partition coefficient being industrial scale, more economically feasible ways a function of the pH in the aqueous phase is often of producing synthetic drugs emerged. This led to exploited in pharmaceutical separations to the invention of separation methods such as increase selectivity when separating a solute that liquid-liquid extraction, chromatography, and is weakly acidic or basic. This method works membrane-based separation techniques. In the based on the principle of pH solubility which is the following section, these techniques along with result of the solute dissociating in the aqueous their principles will be explored. phase but not the organic phase, which effectively traps the ionized solute in the aqueous phase (depicted in Figure 3). This technique is used in processes such as the extraction of penicillin which is a weak acid [3]. 2 Chemical Engineering Unit Operations – Term Paper design, this type of extractor could reach an efficiency of 0.8-0.9 theoretical stage units for every actual unit [5]. Figure 2 Equilibrium curve depicting the relationship between solute concentration in the solvent versus the concentration in the feed [3] Figure 4 Schematic Diagram of the mixer and settler in a stagewise extractor [6] Figure 5 Multistage mixer-settler setup in counter-current LLE [7] Figure 3 Diagram depicting the partitioning of a weak acid As opposed to stagewise extractors, differential HA between an organic and aqueous phase [4] extractors do not have distinct equilibrium stages. A differential extractor is to a stagewise extractor LLE could be carried out in two different types in a similar way to how a distillation column is to a of extractor – stagewise extractors or differential series of flash tanks. There are many different extractors. Stagewise extractors are small-scale variants of the differential extractor, however, operations that involve a tank and a decanter mechanically agitated and centrifugal extractors (depicted in Figure 4). The operation of a stage- are the most common. A variant of an agitated wise extractor consists of three steps – (i) mixing extractor called a Kühni column is shown in Figure and agitation of the feed and solvent mixture, (ii) 6 to demonstrate how a differential column allowing the mixture to phase separate, and finally operates. In a Kühni column, the lighter liquid (ii) decanting the phase on top of the mixture. The phase is pumped into the column from the bottom recycling of the raffinate (the feed after an LLE while the heavier liquid phase is pumped in from extraction) is possible using this set-up. the top in a counter-current fashion. As the lighter Additionally, the efficiency of LLE could be liquid phase passes through the column, it is enhanced by adopting a countercurrent broken up into small droplets by the agitation in the configuration of the extractors in multi-stage column. This then facilitates the mass transfer of extraction (depicted in Figure 5). With proper solutes from the feed to the solvent. 3 Chemical Engineering Unit Operations – Term Paper Where, 푆 is the flowrate of the solvent, 퐾퐼 is the overall hypothetical equilibrium mass transfer coefficient, 푎 is the interfacial area per unit volume of the column, 퐶퐼 is the bulk concentration of solute in the light liquid phase, 퐶퐼∗ is the concentration of solute in the light liquid phase at the interfacial boundary during equilibrium. Figure 6 Schematic diagram of a variant of the differential extractor-a Kühni extractor [8] The values of NTU and HTU could be used as a measure of the difficulty of the separation and the The overall effectiveness of a differential separation effectiveness of the mass transfer in extractor can be evaluated by calculating the the process. theoretical column height required for a specific Some of the performance parameters of the degree of separation using the method of transfer most common variants of differential extractors units. In this method, the theoretical column height are summarized in table 1. required for the intended separation can be expressed as: ℎ = 퐻푇푈 ∗ 퐻푇푈 Where, 퐻푇푈 is the number of transfer units required, 푁푇푈 is the height of a transfer unit. The value of HTU and NTU can be expressed as: 푆 퐻푇푈 = 퐾퐼푎 퐶퐼,표푢푡 푑퐶 푁푇푈 = ∫ 퐼 (퐶 − 퐶 ) 퐶퐼,푖푛 퐼∗ 퐼 4 Table 1 Typical performance parameter for most common commercial extraction towers Extractor Type Capacity of Spacing Overall Height Plate Efficiency, Height of Ref. Combined between Stages, of Transfer EO, % Equilibrium Streams, T, cm Unit, HOL, m Stage, HETS, m (VD + VC), m3/m2 ° h Spray Tower 15–75 3–6 3–6 [9], [10] Packed Tower 12–30 0.9–1.7 0.4–1.5 [11], [10], [12] Structured 65–90 0.5–1.6 [13] Packing Tower Sieve-Tray 27–60 10–25 8–30 0.8–1.2 [9], [14], [11] Tower Pulsed Packed 17–23 0.15–0.3 [14], [11], [12] Tower Pulsed Sieve 25–35 5.1 0.15–0.3 [11], [12] Tray Tower Scheibel Tower 10–14[*] 2.5–20 0.1–0.3 [14], [15], [16], [12] Karr Tower 30–40 5–15 0.2–0.6 [15], [11] [*] Throughput for diameter D1 = 7.6 cm. 3.2 Chromatography less commonly used in the manufacturing of small Chromatography is a frequently used molecule drugs, its use is prevalent in areas such separation technique that has established itself as as chiral separations, large scale synthetic the preferred operation for meeting the purity and peptides, and oligonucleotides purification [18].