Solid State Behavior of Impurities during 'In-Process' Phase Purity

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Communication

Solid State Behavior of Impurities during ‘InProcess’ Phase Purity Analysis of an API Amol G. Dikundwar, Sharmistha Pal, Pema Chodon, Roopa Narasimhamurthy, Prashant Kameshwar, Meenakshi Sundaram, and Hemant Bhutani Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00334 • Publication Date (Web): 24 Jan 2019 Downloaded from http://pubs.acs.org on January 24, 2019

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Organic Process Research & Development

Solid State Behavior of Impurities during ‘In-Process’ Phase Purity Analysis of an API Amol G. Dikundwar,a‡ Sharmistha Pal,b‡ Pema Chodon,b Roopa Narasimhamurthy,a Prashant Kameshwar,b Meenakshi Sundaram,a Hemant Bhutani*c aAnalytical

R&D, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International limited, Bangalore, India

bPharmaceutics,

Biocon Bristol-Myers Squibb Research and Development Center (BBRC),

Syngene International Limited, Biocon Park, Bangalore 560099, India. cAnalytical

R&D, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Bristol-Myers Squibb India Pvt. Ltd., Bangalore 560099, India.

ACS Paragon Plus Environment

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Abstract: Manufacturing a specified polymorphic form of an active pharmaceutical ingredient (API) is of immense importance in the pharmaceutical industry. Crystal polymorphism and transformations among different forms of APIs are studied in detail during process development. While associated impurities in API are characterized in depth for their chemical structures and properties, solid state characteristics of impurities are usually overlooked, mainly because of their presence in low levels. Herein, we discuss a case of a process impurity, BrettPhos oxide (BPO), interfering with in-process phase analysis of an API. The impact of changing the work up procedure on the impurity purging and its effect on solid form analysis of the API is highlighted. Complexities encountered due to interplay between different solid forms of BPO and API are presented. Further, phase behavior of BPO in some common process relevant solvents is established.

KEYWORDS: BrettPhos, BrettPhos oxide, Buchwald-Hartwig C-N coupling, Phase analysis, Phase impurity, Polymorphism


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Polymorphism of specialty chemicals is an important area of research, particularly in the pharmaceutical industry.1-6 Polymorphs of an active pharmaceutical ingredient (API) can exhibit significantly different physicochemical properties potentially affecting quality and efficacy of a drug product leading to significant regulatory and intellectual property implications.7-14 Hence, significant resources are invested on ensuring consistency in manufacturing the desired polymorphic form of an API, with appropriate in-process controls.15-18 An array of analytical techniques including X-ray powder diffraction (XRPD), thermal analyses and spectroscopy are used for such evaluations.19-30 If presence of additional solid phase is suspected in the material, the usual conjecture is that a new crystalline phase of the same compound has appeared. While the possibility of chemical impurities causing the additional phase in XRPD may be considered, the onus lies on first detecting the impurities by other chemical techniques such as high performance liquid chromatography (HPLC). Sometimes such methods may not be able to detect extremely low levels of impurities, unless the methods are selectively developed for the purpose. During early phase of chemical process development, e.g., route scouting, generally, impurities higher than a certain threshold are only evaluated in detail. In this communication, we present a case study highlighting criticality of solid phase behavior of impurities present in low levels (within acceptance limits) and its implications on in-process phase purity analysis of an API. Buchwald-Hartwig reaction is a palladium catalyzed cross coupling reaction of aryl halides with amines and amides used for the synthesis of carbon-nitrogen (C–N) bonds.31-34 Phosphine based ligands are commonly added during such synthesis to improve reaction rates, selectivity, or yield. The reactions are usually performed in appropriate solvents in presence of a base and under nitrogen atmosphere to prevent the oxidation of palladium and phosphine ligand. In the present case, the API, I, was synthesized following a similar reaction pathway as shown in Scheme 1. The


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API, I is known to exist in several polymorphs including multiple solvates and hydrates, of which an anhydrous form, Form B is the desired form. While all the forms of I have been characterized in detail, only relevant forms are discussed in this article for proprietary reasons.

Scheme 1. Palladium catalyzed Buchwald-Hartwig coupling with BrettPhos ([dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl] -2-yl)phosphine]) as phosphine ligand

Following the synthetic step, the solution of I was filtered to remove the extraneous reagents and then concentrated to obtain crude I. For purification, the crude was dissolved in tetrahydrofuran, treated the solution with charcoal, polish filtered the solution followed by swapping with 2-propanol (IPA) at elevated temperature. Finally, water was added as antisolvent to precipitate the purified I. The wet mass was filtered and then dried at 65 to 70 °C overnight. Chemical purity analysis of the purified dried material by HPLC indicated all impurities to be within acceptable levels (< 0.2 area percent). XRPD diffractograms were recorded for both wet I and dry I because I is known to have different solid forms in the isolation solvent (IPA:water 1:2 v/v) and in the dried state, namely Form A and Form B, respectively. While in most batches, the diffractograms of wet I and dry I compared well with those of Form A and Form B respectively, in few batches, additional diffraction peaks were observed in the wet I and dry I diffractograms. These additional peaks did not correspond to any of the other known crystalline phases of I, though


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there seemed some similarity with one of the undesired API polymorphs, Form C. Further, the extra peaks observed in wet I were different from those observed in dry I. Figure 1 below shows the overlay of wet and dry in-process samples along with the reference patterns of relevant crystalline forms of the API.

Figure 1. Portion of XRPD overlay of slurry and dry in-process control (IPC) samples with reference powder patterns of different forms of API highlighting occurrence of additional peaks in IPC samples [Form A (expected API form in slurry condition), Form B (expected API form in dry condition) and Form C (undesired crystalline form of API seen occasionally in wet as well as dry conditions)].

A systematic study was ensued to understand the cause of the extra peaks in the diffractograms. A few hypotheses were proposed such as presence of potentially new polymorph of I, or a highly


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crystalline process impurity, or a crystalline API-impurity complex. To evaluate whether the extra peaks could be from a potentially new polymorph of I, dry I was reslurried for 24h in IPA:water followed by drying (65 ºC for 14 hours). Both the reslurried wet material and the dried material therefrom were comparable with wet I and dry I, respectively, with the additional peaks remaining intact after reslurrying. Also, as Form A is known to be the most stable form of API I in IPA:water (1:2 v/v) and Form B in the dried state, a competitive slurry experiment was performed wherein dry I was added to the saturated slurry of pure Form A and the mixture was further slurried for 7 days. Samples from both wet and dry conditions were found to be comparable to wet I and dry I with respective additional peaks present in both the samples (see ESI for details). Changes observed in patterns constituted by the additional peaks during reslurrying and drying without impacting corresponding wet and dry patterns of the API suggested the extra peaks are not due to new polymorph of I. Nuclear magnetic resonance (NMR) spectroscopy performed on dry I indicated presence of a phosphorus-containing compound but the spectrum did not seem to match with that of an obvious suspect―the phosphine ligand used in the reaction, BrettPhos (BP; [dicyclohexyl(2',4',6'triisopropyl-3,6-dimethoxy-[1,1'-biphenyl] -2-yl)phosphine] or any other phosphorous-containing degradant of the API. Since the HPLC method, available at that time, had not indicated any phosphorus-containing compound, the method was redeveloped. The modified HPLC method showed presence of BrettPhos-oxide (BPO) in the isolated wet and dry I with no new API related impurities, whenever the extra peaks were observed in XRPD. Figure 2 shows the NMR and HPLC results showing the presence of BPO in dry I. These results suggested the additional phases in wet I and dry I could be due to BPO, either as an independent phase and/or in the form of molecular complex with the API.


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Figure 2. (a) 31P NMR and (b) HPLC comparison of BrettPhos (BP), BrettPhos oxide (BPO) and dry in-process sample indicating presence of BPO in Dry I.

To determine whether the extra peaks were caused by BPO or its complex with the API, at first the solid phase landscape of BPO was evaluated in detail. Both commercially available BP and inhouse synthesized BPO were found to be crystalline in nature, their XRPD patterns are termed Form I (BP) and Form I (BPO), respectively. Since the additional peaks in wet I and dry I were different, possibility of polymorphism in BPO was investigated by slurrying it in the reaction solvent, i. e., IPA:water (1:2 v/v) and in a few selected solvents. Both wet and dried samples from these slurries were analyzed by XRPD and the results are shown in Table 1 and Figure 3. Multiple forms obtained from different solvent systems indicate high propensity for polymorphism of BPO. BP was also slurried in the same set of solvents, however, only one form (Form I) was observed in all the slurries (minor differences were noticed for slurry in chloroform). Chemical integrity of the solids exhibiting the different XRPD patterns was confirmed by HPLC analysis of these solids.


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Table 1. Solid forms of BrettPhos-oxide after slurrying in various solvents at 25 °C and drying at 65 °C XRPD pattern Solvent

Wet

Dry

Acetonitrile

Form I

Form I

Ethyl acetate

Form I

Form I

Methanol

Form IIa

Form I

Acetonitrile:water (1:1 v/v) Form IIIb

Form I + Form III

2-Propanol

Form IVc

Form I

2-Propanol:water (1:2 v/v)

Form IV

Form I

Acetone

Form IV typed

Form I

Methanol:water (1:1 v/v)

Form IV typed

Form I

Chloroform

Form Ve

Form I

Water

Form I + Form VIf Form I + Form VI

Crystal structure details: aHydrate, BPO-H1 (monohydrate, CSD Refcode: KAMSEZ); bHydrate, BPO-H2 (monohydrate, CSD Refcode: KAMSEZ01); cIPA solvate, BPO-IPA (monoisopropanol solvate, Refcode: KAMSOJ); dXRPD is similar to Form IV but with few non-systematic shifts (may be isostructural solvate/hydrate to IPA solvate); eCHCl3 solvate, BPO-CH (monochloroform solvate, Refcode: KAMSUP); fFew minor peaks observed with Form I as a majority phase, these peaks diminish upon drying.


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Figure 3. XRPD overlay of BrettPhos Form-I (BP-I) and different crystalline forms of BrettPhos oxide, BPO-I to BPO-VI (BPO-VI pattern is a mixture of Form I with a few minor extra peaks).

The slurries of BPO in acetonitrile and ethyl acetate compared well with that of the starting form, i.e., Form I, while the XRPD patterns of the other wet slurries indicated new forms, Forms II-VI. For most of these crystalline forms, structures could be solved by single crystal X-ray diffraction (reported elsewhere).35 Form I of BPO is a neat form, Forms II and III are hydrates, Form IV is an IPA solvate and Form V is a chloroform solvate. Form VI pattern appears to be a physical mixture with Form I as a majority phase containing few peaks from a new minority phase. In all these hydrates and solvates, water or solvent molecules are linked to BPO molecules via P=O∙∙∙H


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hydrogen bond.35 Interestingly, all the hydrate/solvate forms (II-VI) of BPO tend to transform to the neat form (Form I) upon drying (65 °C ). The differing intermolecular interaction patterns in the known structures suggest, however, that the kinetics of desolvation may vary among the different forms, which can be explored further. Figure 4 provides a schematic representation for the observed solvation and desolvation behavior of BPO. PXRD overlays of respective simulated and experimental patterns and chemical purity analysis by HPLC are provided in the supplementary information.

Figure 4. Schematic representation of BPO solvate/hydrate formation resulting in a new crystalline form which on heat drying converts back to the starting desolvated form.

Based on the results from polymorph screening of BPO, it is evident that BPO forms an IPA solvate, Form IV, in the process solvent IPA:water (1:2 v/v), which on drying converts to Form I. The reversible inter-conversion between these two forms of BPO was also confirmed by performing two cycles of IPA:water (1:2 v/v) slurry followed by drying on the same material, where complete conversions were observed (see ESI for details). It is to be noted that, the characteristic peaks of Form IV (2θ 9.0°, 10.2°, 10.3°, 13.1°, 13.5°, 18.5° and 18.8°) compare well


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with the extra peaks in wet I, while the characteristic peaks of Form I (2θ 8.8°, 9.6°, 12.8°, 13.2°, 20.1° and 21.0°) compare well with that of the additional phase in dry I. Notably, addition of small amount (~1% w/w, corresponding to levels in scale-up batch) of BPO Form I into the slurry of clean API I confirmed occurrence and detection of some of these major unique peaks in respective wet and dry condition samples (see ESI for details). This confirmed that occurrence of distinct extraneous peaks in the wet I and dry I patterns were due to ‘in-process’ conversion of crystalline forms of BPO (IPA solvate to non-solvated form and vice-versa) and in turn ruled out the possibility of formation of an API-BPO molecular complex. Although BPO polymorphs was confirmed to be cause of the extra peaks in the diffractogram of the API, an understanding of the reason for the sporadic occurrence of the peaks was required to develop a control strategy to purge the impurity. Investigations indicated that the efficiency and kinetics of removal of the palladium catalyst and BP during the purification step with charcoal treatment under nitrogen atmosphere was critical in determining whether BPO would appear in the final API. While the nitrogen atmosphere during Buchward-Hartwig step prevented oxidation of BP during the synthesis, absence of nitrogen blanket during the purification step meant that BPO formation increased when time required for removal of palladium catalyst and BP was longer. When the efficiency of the charcoal treatment for purification was high and the kinetics of BP removal was fast, BPO formation was not observed, while when the kinetics and efficiency of BP removal was compromised, chances of BPO formation in the final API increased. Since BPO has negligible solubility in water, addition of water during the final precipitation of I results in coprecipitation of BPO along with the API. Thus, development of an efficient purification step and performing the purification under nitrogen atmosphere helped in mitigating the risk of observing extraneous peaks in the final API. It is noted that the knowledge about phase behavior of BP and


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BPO and their respective XRPD profiles in various process relevant solvents may serve as useful guide during process development where presence of these reagents/impurities is suspected.

CONCLUSION The intent of this communication is to highlight three points, i.e., (a) nonconformance in XRPD patterns observed during in-process analysis may not necessarily be due to a new crystalline phase of the compound but could also be due to impurities, (b) the impurities whose peaks appear in the XRPD may be process related derivatives or degradants of any of the reagents used in the process, (c) impurities and their derivatives/degradants may show polymorphism or pseudo-polymorphism themselves. While the above assertions are true in general for any analytical technique, in our experience, less attention is paid to solid phase nature of impurities during phase purity analysis of a compound. One of the reasons for overlooking this aspect may be the drive to produce highly pure material for commercial purpose. The purport of the present work is to highlight that a sufficiently pure material meeting specifications with respect to chemical impurities may also exhibit mixed phases, which in reality could be due to polymorphism of impurities. Such consideration becomes crucial from phase analysis point of view, particularly for the impurities which are highly crystalline in nature.

ASSOCIATED CONTENT Supporting Information. The following files are available free of charge. Materials and Methods; Crystal structure details of BrettPhos oxide (BPO) and solvatomorphs of BPO (BPO-H1, BPO-H2, BPO-IPA and BPO-CH); XRPD overlays and Purity analysis data (PDF).


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AUTHOR INFORMATION Corresponding Author * [email protected]; [email protected]. Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally.

ACKNOWLEDGMENT Authors are thankful to Tamilarasan Subramani and Somanadham Mummadi for the synthesis of BrettPhos oxide and Rudra Sahu and Saravanan Natarajan for HPLC analyses.

ABBREVIATIONS API, Active Pharmaceutical Ingredient; BP, BrettPhos; BPO, BrettPhos Oxide; HPLC, High Performance Liquid Chromatography; NMR, Nuclear Magnetic Resonance


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Solid State Behavior of Impurities during 'In-Process' Phase Purity

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