Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time

Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Pu, Siyu [verfasserIn] Hadinoto, Kunn [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth

Übergeordnetes Werk:	Enthalten in: Chemical engineering science - Amsterdam [u.a.] : Elsevier Science, 1951, 230
Übergeordnetes Werk:	volume:230

DOI / URN:	10.1016/j.ces.2020.116181

Katalog-ID:	ELV005190193

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245	1	0	\|a Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time
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520			\|a Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively.
650		4	\|a Protein crystallization
650		4	\|a Continuous crystallization
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650		4	\|a Pharmaceuticals
650		4	\|a Crystal growth
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allfields	10.1016/j.ces.2020.116181 doi (DE-627)ELV005190193 (ELSEVIER)S0009-2509(20)30713-2 DE-627 ger DE-627 rda eng 660 DE-600 58.14 bkl Pu, Siyu verfasserin aut Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively. Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth Hadinoto, Kunn verfasserin aut Enthalten in Chemical engineering science Amsterdam [u.a.] : Elsevier Science, 1951 230 Online-Ressource (DE-627)306717794 (DE-600)1501538-5 (DE-576)094503982 nnns volume:230 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 58.14 Chemische Reaktionstechnik AR 230
spelling	10.1016/j.ces.2020.116181 doi (DE-627)ELV005190193 (ELSEVIER)S0009-2509(20)30713-2 DE-627 ger DE-627 rda eng 660 DE-600 58.14 bkl Pu, Siyu verfasserin aut Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively. Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth Hadinoto, Kunn verfasserin aut Enthalten in Chemical engineering science Amsterdam [u.a.] : Elsevier Science, 1951 230 Online-Ressource (DE-627)306717794 (DE-600)1501538-5 (DE-576)094503982 nnns volume:230 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 58.14 Chemische Reaktionstechnik AR 230
allfields_unstemmed	10.1016/j.ces.2020.116181 doi (DE-627)ELV005190193 (ELSEVIER)S0009-2509(20)30713-2 DE-627 ger DE-627 rda eng 660 DE-600 58.14 bkl Pu, Siyu verfasserin aut Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively. Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth Hadinoto, Kunn verfasserin aut Enthalten in Chemical engineering science Amsterdam [u.a.] : Elsevier Science, 1951 230 Online-Ressource (DE-627)306717794 (DE-600)1501538-5 (DE-576)094503982 nnns volume:230 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 58.14 Chemische Reaktionstechnik AR 230
allfieldsGer	10.1016/j.ces.2020.116181 doi (DE-627)ELV005190193 (ELSEVIER)S0009-2509(20)30713-2 DE-627 ger DE-627 rda eng 660 DE-600 58.14 bkl Pu, Siyu verfasserin aut Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively. Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth Hadinoto, Kunn verfasserin aut Enthalten in Chemical engineering science Amsterdam [u.a.] : Elsevier Science, 1951 230 Online-Ressource (DE-627)306717794 (DE-600)1501538-5 (DE-576)094503982 nnns volume:230 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 58.14 Chemische Reaktionstechnik AR 230
allfieldsSound	10.1016/j.ces.2020.116181 doi (DE-627)ELV005190193 (ELSEVIER)S0009-2509(20)30713-2 DE-627 ger DE-627 rda eng 660 DE-600 58.14 bkl Pu, Siyu verfasserin aut Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively. Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth Hadinoto, Kunn verfasserin aut Enthalten in Chemical engineering science Amsterdam [u.a.] : Elsevier Science, 1951 230 Online-Ressource (DE-627)306717794 (DE-600)1501538-5 (DE-576)094503982 nnns volume:230 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 58.14 Chemische Reaktionstechnik AR 230
language	English
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topic_facet	Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth
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author	Pu, Siyu
spellingShingle	Pu, Siyu ddc 660 bkl 58.14 misc Protein crystallization misc Continuous crystallization misc Lysozyme misc Pharmaceuticals misc Crystal growth Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time
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topic_title	660 DE-600 58.14 bkl Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time Protein crystallization Continuous crystallization Lysozyme Pharmaceuticals Crystal growth
topic	ddc 660 bkl 58.14 misc Protein crystallization misc Continuous crystallization misc Lysozyme misc Pharmaceuticals misc Crystal growth
topic_unstemmed	ddc 660 bkl 58.14 misc Protein crystallization misc Continuous crystallization misc Lysozyme misc Pharmaceuticals misc Crystal growth
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title	Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time
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title_full	Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time
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title_sort	improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time
title_auth	Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time
abstract	Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively.
abstractGer	Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively.
abstract_unstemmed	Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively.
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title_short	Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time
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Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time

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