Use of a Polymer Additive To Enhance Impurity Rejection in the

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Use of a Polymer Additive to Enhance Impurity Rejection in the Crystallization of a Pharmaceutical Compound Ann Marie Czyzewski, Shuang Chen, Venkateswarlu Bhamidi, Su Yu, Ian Marsden, Chen Ding, Calvin Becker, and James Napier Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00145 • Publication Date (Web): 24 Aug 2017 Downloaded from http://pubs.acs.org on August 25, 2017

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Organic Process Research & Development

Use of a Polymer Additive to Enhance Impurity Rejection in the Crystallization of a Pharmaceutical Compound

Ann M. Czyzewski*,1, Shuang Chen*,1,§, Venkateswarlu Bhamidi 1,†, Su Yu 1, Ian Marsden 2, Chen Ding 1, Calvin Becker 1, James J. Napier 1 1

Process Research & Development, 2 Structural Chemistry, AbbVie Inc., 1401 Sheridan Road, North Chicago, IL 60064

Corresponding Authors: Ann M. Czyzewski,

(847) 937-8671

Shuang Chen

[email protected] [email protected]

§

†Present Address Scale-up and Process Innovation Eastman Chemical Company Kingsport, TN 37662-5167, USA

Present Address Pharmaceutical Development & Manufacturing Sciences, Janssen Research & Development 65 Guiqing Rd., Xuhui District, Shanghai 200233, China

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Abstract

Control of impurity content in active pharmaceutical ingredients is of utmost importance for the pharmaceutical industry. While crystallization is oftentimes used as an efficient and costeffective means of achieving this purification, structurally similar impurities can be very difficult to separate via crystallization. The impact of non-adsorbing polymers on the crystallization of the compound of interest can be leveraged to enhance purification of pharmaceutical molecules. Here we discuss a case study in which an impurity formed in a pilot plant batch at a level of 3% could not be adequately rejected using conventional crystallization processes. We used a polymer additive to modify the crystallization to enhance impurity rejection. The process was implemented on scale to successfully deliver the product with less than 0.1% of the impurity. We explain the observed influence of the polymer additive on the crystallization of the product by carrying out additional investigations and considering the effect of the additive on the energy barrier to nucleation and growth kinetics of the impurity crystals. This work demonstrates the utility of polymer additives in crystallization process development of pharmaceutical compounds.

Keywords: pharmaceutical crystallization, crystallization, impurity rejection, crystallization additives, non-adsorbing polymers, nucleation suppression.



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1. Introduction Process and drug-related organic impurities arise from many sources throughout the synthesis of active pharmaceutical ingredients (APIs). These impurities include the starting materials, intermediates, by-products, catalysts and ligands, reagents, enantiomeric compounds, and degradation products.1-3 These impurities, if present in the drug substance even at extremely low levels, can result in concerns regarding the safety of the drug product. This concern has prompted the pharmaceutical industry to prioritize the development of manufacturing processes that strictly control impurities at appropriately designated levels, as required by various international regulatory agencies.4-6 Significant resources are invested during API process development in both understanding the mechanisms of impurity formation as well as in maximizing the process capability for impurity rejection.7 Selective crystallization of a drug substance from a solution that contains several impurities is one of the most efficient and cost-effective separation and purification operations used in pharmaceutical manufacturing.8 The impurities that are removed by crystallization can be related in molecular structure to the drug substance (such as dimers, incomplete reaction products, side products, etc.), or they may be of a very different class of molecules that are present in the process (such as solvents, catalyst molecules etc.). Conventional crystallization, however, sometimes can be ineffective in separating the API from some structurally-related impurities due to the similarity in the physicochemical properties of the desired product and impurity molecules. Non-adsorbing polymers (polymers that do not react with the solute molecule, but influence the intermolecular interactions) fundamentally modify the crystallization process of a compound by affecting its thermodynamic solubility as well as the crystal nucleation and growth kinetics.9-14 The effectiveness of polymers in slowing down crystallization kinetics of crystalline materials and in stabilizing supersaturated solutions of amorphous materials during


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dissolution has been discussed in the literature.15 Polymeric additives are also known to affect many properties of the resultant crystals, including crystal polymorphism and habit, particle size, and the intrinsic dissolution rate.12-14,

16

In this work, we present a case study that

demonstrates the effectiveness of this technique in enhancing the ability of a crystallization process to reject an otherwise poorly-rejected impurity. The separation challenge we discuss in this work arose during a cGMP pilot plant run to produce 48 kg of pharmaceutical intermediate, Intermediate C. During the work-up of a Sonogashira coupling reaction to produce Intermediate C, a new structurally-related impurity, Impurity D, formed at a level of 3.5 area% by HPLC-UV (Scheme 1) in the reaction mass with an otherwise typical impurity profile (other total impurities ~0.5%). The presence of an acid in the work-up, in combination with high temperature, unexpectedly catalyzed a ring-closing reaction that formed the impurity. Upon the discovery of the impurity, pilot plant processing was halted and Intermediate C was held as a 50 mg/mL (20 mL/g) solution in tetrahydrofuran (THF) until a suitable purification protocol was identified.

Scheme 1. Formation of Impurity D.



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2. Experimental Section 2.1. Materials and Methods Solvents and reagents were purchased from Sigma Aldrich (Saint Louis, Missouri) or similar. Hydroxymethylpropylcellulose (HPMC) Pharmacoat grade 606 was purchased from Shin Etsu (Tokyo, Japan). Kollidon® VA 64 (copovidone) was purchased from BASF (Ludwigshafen, Germany). Process exploration experiments were performed in temperature-controlled jacketed vessels equipped with overhead stirring. Distillations were performed under vacuum within the jacketed vessel or using rotary evaporation. Controlled additions of antisolvents were made using a Scilog pump (Scilog Bioprocessing Systems, Madison, WI) or an addition funnel. Products were filtered on sintered glass funnels and were dried in a vacuum oven (Thermo Fisher Scientific, Waltham Massachusetts).

2.2. Solubility/Concentration Measurements Equilibrium solubility was determined by measuring the concentration of each species in supernatant using HPLC after equilibration of the slurry for more than ten days at the target condition. Samples taken from a crystallization mixture to measure the product and impurity desupersaturation profiles were withdrawn from a stirred jacketed reactor at specified times and were immediately filtered into a tared volumetric flask and diluted for HPLC analysis.

2.3. Powder X-ray Diffraction (PXRD) We prepared the samples for PXRD analysis by spreading the sample powder (~5 to 10 mg) in a thin layer on an aluminum sample holder and gently leveling with a glass microscope slide. The aluminum sample holder was then mounted on the rotating sample holder of an XRG 3000 diffractometer (Inel Corp., Artenay, France) and diffraction data were collected at ambient


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conditions. The XRG 3000 diffractometer was equipped with a curved position sensitive detector and parallel beam optics and was operated with a copper anode tube (1.5 kW fine focus) at 40 kV and 30 mA. A germanium monochromator provided the monochromatic Cu Kα1 radiation (λ = 1.54056 Å). We calibrated the diffractometer using the attenuated direct beam at one-degree intervals. Calibration was checked using a silicon powder line position reference standard (NIST 640c). The instrument was computer controlled using the Symphonix 1.0 software (Inel Corp., Artenay, France). We analyzed the data with Jade 9.0 software (Materials Data, Inc., Livermore, CA).

3. Results 3.1. Evaluation of processing alternatives Upon the discovery of the impurity formation in the batch, we performed several laboratory experiments to evaluate paths forward for achieving a satisfactory rejection of Impurity D through crystallization. Taking the product solution through the originally-planned Intermediate C crystallization followed by the remaining synthesis steps for the API resulted in an Impurity D content of 1.7 area% in the final API, thus failing the single largest unspecified impurity limit of not more than 0.1%. Alternative crystallization conditions were explored, including antisolvents that exhibit a range of polarity (methanol, water, isopropanol, acetonitrile, dimethyl ether, 2-MeTHF, toluene, methyl-tert-butyl ether, and dimethylacetamide) and temperatures commensurate with product stability (0 to 70 °C). These solvents were evaluated alone and in various combinations with the goal of affording acceptable impurity rejection while maintaining acceptable product yield. Because THF was unique in affording reasonable solubility of Intermediate C, alternative solvent choices for readily solubilizing the product were not available. At all conditions evaluated, we found that the equilibrium solubility of Impurity D was consistently lower than that of Intermediate C. This lower solubility of Impurity D in comparison to that of Intermediate C caused Impurity D to crystallize earlier than 6 Environment ACS Paragon Plus


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Figure 1. General protocol for antisolvent crystallization

Intermediate C at any solution condition, and thus compromised the impurity rejection capacity of any conceived crystallization scheme. Our subsequent efforts to crystallize salts of the intermediate using various counterions in a similar range of solvent conditions also resulted in insufficient impurity rejection, with 1.8 – 3.0 area% impurity remaining in the isolated intermediate. The most promising crystallization protocol evolved from over 60 screening experiments was an antisolvent crystallization process, shown schematically in Figure 1. The general process to distill the product mixture to 6 mL/g and then add 24 mL/g of antisolvent was based on the minimum volume required to maintain a well-stirred slurry and on the need to add enough antisolvent to produce acceptable product yield (>80%). The several antisolvents and the range of processing temperatures explored using this basic process design all yielded product with unacceptable levels of Impurity D, thus demonstrating the ineffectiveness of the crystallization methods explored in affording adequate impurity rejection. 3.1.1. Dynamics of impurity crystallization Crystallization of Impurity D exhibited a characteristic kinetic profile across several solvent systems studied. Upon distilling the product to 6 mL/g of THF solution, Intermediate C began to crystallize, while Impurity D remained in solution (monitored for up to 3 days). Upon completing the addition of antisolvent, Impurity D initially remained solubilized, but invariably


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began to crystallize within a few hours in gram-scale lab experiments, thus compromising the efficacy of crystallization in purifying the product at a large scale. We estimated this induction period in the onset of crystallization of Impurity D by periodically assaying the samples of mother liquor for Impurity D and Intermediate C using HPLC (see Figure 4(b) below for a specific case). Powder X-ray diffraction (PXRD) patterns of the solids isolated at various time points during the crystallization suggested the occurrence of a polymorphic transformation of the Intermediate C after the antisolvent addition. Out of the 6 mL THF/g solution, Intermediate C crystallized as a THF solvate, Form II. Upon the completion of antisolvent addition, these crystals transformed to a non-solvated form, Form I (see Figure 2 below for PXRD patterns). Moreover, experiments revealed that this transformation takes place well before the onset of crystallization of Impurity D, a result that suggests that the impurity was not being selectively incorporated into the crystal of Form I, but was crystallizing on its own.

Figure 2. Powder X-ray diffraction patterns of Forms I (non-solvate), II (THF solvate), and III (solvate) of Intermediate C crystals. Form III first appeared in the presence of polymer being present in the crystallization system.



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Based on this process information obtained, we conceived two possible options for isolating the product in the pilot plant run: (a) Isolate Intermediate C as Form II crystals from THF alone – this option offers good impurity rejection, but results in a very low yield of product (80%) antisolvent crystallization in which the degree of Impurity D rejection would be unpredictable due to its dependence on the nucleation kinetics. The high yield associated with the second option prompted investigation into whether the crystallization kinetics of Impurity D can be modified such that its nucleation is inhibited over a time frame sufficient for isolating the crystallized product C on the pilot plant scale, thus enabling efficient removal of Impurity D in the filtrate. 3.1.2. Polymer as a crystallization inhibitor – proof of concept Small amounts of polymer additives are known to significantly impact crystallization processes as well as resultant crystal properties.9-12 Hence, we explored the possibility of slowing down the crystallization kinetics of Impurity D using a polymer additive in the antisolvent crystallization process described previously. Initial proof-of-concept experiments were performed using hydroxypropylmethyl cellulose (HPMC) or copovidone (Kollidon® VA 64) as the additive. These polymers were selected based on their good solubility in some organic solvents and their prevalent use in drug product formulation. We designed the initial proof-of-concept crystallization experiments in accordance with the process scheme described in Figure 1 using isopropanol (i-PrOH) as an antisolvent. Isopropanol was chosen as an antisolvent due to the low solubility of Intermediate C in it, and for its ability to dissolve known impurities. Polymer (12 w/w% based on Intermediate C content) was added to the THF product solution prior to distillation. Addition of HPMC to the product solution caused the solution to become viscous and the isolated solids to be sticky and difficult to dry. Addition of copovidone to the reaction mixture caused no observable change in the appearance of either the crystallization mixture or the isolated solids. Moreover, the isolated solids


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contained 0.1%) affected the crystallization of Impurity D strongly, and a minimum of about 1.5 w/w% of copovidone was needed in order produce Intermediate C with

Use of a Polymer Additive To Enhance Impurity Rejection in the

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