CN105616415B - 一种注射用哌拉西林钠他唑巴坦钠的制备方法 - Google Patents
一种注射用哌拉西林钠他唑巴坦钠的制备方法 Download PDFInfo
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- TUPFOYXHAYOHIB-YCAIQWGJSA-M sodium;(2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]h Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 TUPFOYXHAYOHIB-YCAIQWGJSA-M 0.000 title claims abstract description 19
- 238000002347 injection Methods 0.000 title claims abstract description 15
- 239000007924 injection Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 53
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 39
- 229960003865 tazobactam Drugs 0.000 claims abstract description 21
- 239000000243 solution Substances 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 17
- 229960002292 piperacillin Drugs 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims abstract description 12
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 239000000843 powder Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 5
- 239000000284 extract Substances 0.000 claims abstract description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- -1 Piperacillin acid Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 abstract description 16
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 abstract description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 7
- 150000003839 salts Chemical class 0.000 abstract description 5
- 238000000354 decomposition reaction Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 13
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 7
- 229960000373 tazobactam sodium Drugs 0.000 description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- 239000003781 beta lactamase inhibitor Substances 0.000 description 3
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 235000021050 feed intake Nutrition 0.000 description 3
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960005264 piperacillin sodium Drugs 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003462 zymogenic effect Effects 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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Abstract
本发明公开了一种注射用哌拉西林钠他唑巴坦钠的制备方法。它是将配料罐内加入水,降温至5~10℃加入柠檬酸后再缓慢加入碳酸氢钠,待反应完成后读取pH并调整pH 6.3‑6.6;将哌拉西林酸加入配料罐内,然后滴加碳酸氢钠溶液,控制滴加过程中pH≤7.0;滴加完毕后继续加入他唑巴坦酸,然后滴加碳酸氢钠溶液,控制滴加过程中pH≤7.0;滴加完毕后,真空抽除二氧化碳气体,配料罐内的料液平稳后读取pH并调整pH 6.0‑6.5;除菌过滤,冻干得到注射用哌拉西林钠他唑巴坦钠原粉。本发明通过加入柠檬酸成盐,提高产品的酸度稳定性,抑制了哌拉西林钠和他唑巴坦钠的分解,提高了产品的贮存稳定性。
Description
技术领域
本发明涉及一种注射用哌拉西林钠他唑巴坦钠(8:1)的制备方法,属于医药技术领域。
背景技术
他唑巴坦钠是日本大鹏制药公司开发的新型青霉烷砜类β-内酰胺酶抑制剂,是目前临床应用效果最好的β-内酰胺酶抑制剂之一,具有稳定性高,活性低,毒性低,抑酶活性强等特点。哌拉西林钠是第二代半合成β-内酰胺类抗生素的优良品种,具有抗菌谱广,抗菌作用强,毒副作用轻、且对严重革兰氏阴性杆菌感染伴有肾功能损害者尤为适用等特点,已在临床广泛使用。合用强力的β-内酰胺酶抑制剂他唑巴坦钠和广谱的半合成青霉素哌拉西林钠是解决耐药菌的较理想选择。注射用哌拉西林钠和他唑巴坦钠复方制剂中,哌拉西林与他唑巴坦的配比有8:1和4:1两种。配比为8:1的复方制剂最初由日本大鹏公司(Taiho)研究,美国Lederle公司最先获得8:1许可证,于1992年首先在法国上市,1993年后相继在英国、西班牙、德国和美国等国家上市,用于成人及12岁以上儿童产酶菌所致感染的治疗。
现有生产注射用哌拉西林钠他唑巴坦钠冻干制剂普遍采用哌拉西林酸、他唑巴坦酸和碳酸氢钠作为反应原辅料进行生产,具体工艺如下:将哌拉西林酸和他唑巴坦钠加入配料罐内,滴加碳酸氢钠碱液;反应过程中或反应完成后开启真空抽除二氧化碳气体,然后每半小时进行料液澄清度和pH的检查,并根据情况调节pH在5.0-7.0之间且料液澄清。料液经过滤器过滤后,再通过灌装泵灌入西林瓶,进一步冻干制备成哌拉西林钠他唑巴坦钠(8:1)冻干粉。上述方法制备的冻干制剂在贮存24个月后,哌拉西林钠和他唑巴坦钠的含量明显降低,pH明显降低,其产品的稳定性有待进一步改善。
发明内容
本发明克服了上述现有技术的固有流程,提供了一种注射用哌拉西林钠他唑巴坦钠的制备方法。该方法首先在反应罐内投入柠檬酸和碳酸氢钠,调节好pH后,再加入哌拉西林酸、他唑巴坦酸,同时滴加相应成盐使用的碳酸氢钠,投料结束后抽真空反应。该方法提高了产物的贮存稳定性。
本发明的技术方案是:一种注射用哌拉西林钠他唑巴坦钠的制备方法,其特征是,
(1)将配料罐内加入水(作为底水),降温至5~10℃,加入柠檬酸,搅拌均匀后缓慢加入碳酸氢钠(控制加碱时间≥20分钟),待反应完成后(加完碳酸氢钠后≥10分钟)读取pH,然后调整pH 6.3-6.6之间(如pH低于6.3,则加入碳酸氢钠进行调节;如果pH值高于6.6,则加入柠檬酸进行调节);
(2)控温5~10℃,将哌拉西林酸加入步骤(1)的配料罐内,然后滴加浓度为12-16%的碳酸氢钠溶液(用于哌拉西林酸成盐),控制滴加过程中pH≤7.0;
(3)滴加完毕后,控温5~10℃继续加入他唑巴坦酸,然后滴加浓度为12-16%的碳酸氢钠溶液(用于他唑巴坦酸成盐),控制滴加过程中pH≤7.0;
(4)滴加完毕后,控温5~10℃开启真空抽除二氧化碳气体,控制真空的压力≤-0.085Mpa(-0.085Mpa~-0.10Mpa);配料罐内的料液平稳后(投料后≥1小时)读取pH,并调整pH为6.0-6.5之间(如果pH低于6.0加入碳酸氢钠溶液调节,使其充分反应30分钟,再读取pH值,如果pH值仍低于6.0,则再次加入碳酸氢钠溶液,使其反应,循环此过程直到pH符合要求);
(5)除菌过滤,冻干得到注射用哌拉西林钠他唑巴坦钠(8:1)原粉。
所述产物中哌拉西林钠和他唑巴坦钠的质量比8:1。其中哌拉西林酸用量(Kg):W×8/9÷(1-水分)÷(哌拉西林含量-A%);A:根据工艺标准调整系数。他唑巴坦酸用量(Kg):W×1/9÷(1-水分)÷含量×1.025,其中W为产物中哌拉西林钠他唑巴坦钠质量(折纯)。
所述柠檬酸与他唑巴坦酸的质量比为0.28-0.30:1。
本发明步骤(4)的最终料液浓度为35-40%,步骤(1)的底水(注射用水)(L)=总体积-出粉体积-碳酸氢钠溶液体积。总体积(L):实际投料量÷配制浓度%。
优选的,所述步骤(1)柠檬酸与碳酸氢钠的质量比为4.28:5.14。
优选的,所述步骤(2)哌拉西林酸与碳酸氢钠的摩尔比为1:1~1.02。
优选的,所述步骤(3)他唑巴坦酸和碳酸氢钠的摩尔比为1:1~1.02。
优选的,步骤(2)和(3)的碳酸氢钠浓度为13-15%,底水的用量为90-120ml/129kg哌拉西林钠他唑巴坦钠(折纯)。
哌拉西林酸成盐反应:
他唑巴坦酸成盐反应:
柠檬酸成盐反应:
本发明的有益效果是:通过加入柠檬酸成盐,提高产品的酸度稳定性,抑制了哌拉西林钠和他唑巴坦钠的分解,提高了产品的贮存稳定性。同时该方法通过对反应温度、投料比例及反应过程中pH的控制,提高了反应过程中的稳定性和产品的质量。
具体实施方式
本实施例所用原料的哌拉西林酸:水分3.5%,含量99.0%;他唑巴坦酸:水分0.02%,含量99.5%。
实施例1
(1)将配料罐内加入底水102ml,降温到6.5℃;将4.28g柠檬酸投入配料罐中,搅拌10分钟后,开始缓慢加入5.14g碳酸氢钠(控制加碱时间不少于20分钟),10分钟后记录pH,如pH低于6.3,则加入适量的碳酸氢钠进行调节;如果pH值高于6.6,则加入适量的柠檬酸进行调节,最终调整pH 6.40;
(2)控温5~10℃,将125g哌拉西林酸转入配料罐内,然后将浓度为14%的碳酸氢钠溶液(19.40g碳酸氢钠溶于水中配成14%的溶液)滴加到配料罐内,控制滴加过程中pH不要高于7.0;
(3)继续加他唑巴坦14.8g,然后将配制好的14%的碳酸氢钠溶液(4.13g碳酸氢钠溶于水中配成14%的溶液)开始滴加到配料罐内,加入过程中控制配料罐内的温度在5~10℃,控制滴加过程中pH不要高于7.0;
(4)投料完毕,开启真空抽除二氧化碳气体,控制真空的压力≤-0.085Mpa。抽真空一小时后,将反应罐内体积定容。密切观察罐温,罐温应控制保持在5~10℃,每隔10分钟记录一次罐温。投料结束一小时后读取pH,如果pH低于6.0打开罐盖加入14%的碳酸氢钠溶液调节,使其充分反应30分钟,再读取pH值,如果pH值仍低于6.0,则再次适量加入14%的碳酸氢钠溶液,使其反应,循环此过程直到溶液澄清且pH为6.22;
(5)此时料液的浓度为38%,将料液除菌过滤,冻干得哌拉西林钠他唑巴坦钠(8:1)原粉。
实施例2:
(1)底水115ml,降温至6.0℃,加入柠檬酸4.28g和碳酸氢钠5.14g。调节pH6.36;
(2)加入哌拉西林125g,他唑巴坦14.8g,滴加碳酸氢钠:共23.53g(先19.40g和后4.13g,配制成浓度为15%的溶液)。检测最终pH6.25;
(3)此时料液的浓度为38%,将料液除菌过滤,冻干得哌拉西林钠他唑巴坦钠(8:1)原粉。
其余同实施例1。
实施例3:
(1)底水93ml,降温至7.0℃,加入柠檬酸4.28g和碳酸氢钠5.14g,调节pH6.37;
(2)加入哌拉西林125g,他唑巴坦14.8g,滴加碳酸氢钠共23.53g(先19.40g和后4.13g,配制成浓度为13%的溶液)。检测最终pH6.24;
(3)此时料液的浓度为38%,将料液除菌过滤,冻干得哌拉西林钠他唑巴坦钠(8:1)原粉。
其余同实施例1。
本发明实施例1-3的产品与对比例(步骤(1)仅加入底水,即不加柠檬酸和碳酸氢钠,其余同实施例1)的产品的性能指标如表1所示。
表1实施例1-3的产品稳定性数据(24个月)与现有技术的比较表
通过上述反应可以看出:增加柠檬酸后,不影响哌拉西林和他唑巴坦两组份的比例关系,对最终产品的含量没有影响。并且增加柠檬酸后,提高产品的酸度稳定性及其他质量参数。
Claims (4)
1.一种注射用哌拉西林钠他唑巴坦钠的制备方法,其中哌拉西林钠和他唑巴坦钠的质量比为8:1,其特征是,包括以下步骤:
(1)将配料罐内加入水,降温至5~10℃,加入柠檬酸,搅拌均匀后加入碳酸氢钠,控制加碳酸氢钠的时间≥20分钟,待反应完成后读取pH,然后调整pH 6.3-6.6;
(2)控温5~10℃,将哌拉西林酸加入步骤(1)的配料罐内,然后滴加浓度为12-16%的碳酸氢钠溶液,控制滴加过程中pH≤7.0;所述哌拉西林酸与碳酸氢钠的摩尔比为1:1~1.02;
(3)滴加完毕后,控温5~10℃继续加入他唑巴坦酸,然后滴加浓度为12-16%的碳酸氢钠溶液,控制滴加过程中pH≤7.0;所述他唑巴坦酸和碳酸氢钠的摩尔比为1:1~1.02;
(4)滴加完毕后,控温5~10℃开启真空抽除二氧化碳气体,控制真空的压力≤-0.085Mpa;配料罐内的料液平稳后读取pH,并调整pH为6.0-6.5;
(5)除菌过滤,冻干得到注射用哌拉西林钠他唑巴坦钠原粉;
所述柠檬酸与他唑巴坦酸的质量比为0.28-0.30:1。
2.如权利要求1所述的一种注射用哌拉西林钠他唑巴坦钠的制备方法,其特征是,所述步骤(4)的最终料液浓度为35-40%。
3.如权利要求1所述的一种注射用哌拉西林钠他唑巴坦钠的制备方法,其特征是,所述步骤(2)和(3)的碳酸氢钠浓度为13-15%。
4.如权利要求1-3中任意一项所述的一种注射用哌拉西林钠他唑巴坦钠的制备方法,其特征是,所述步骤(1)如pH低于6.3,则加入碳酸氢钠进行调节;如果pH值高于6.6,则加入柠檬酸进行调节。
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