WO2015159236A1 - Polymorphic forms of 4,5-dihydro-1h-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid and its disodium salt, process for their preparation and their use - Google Patents
Polymorphic forms of 4,5-dihydro-1h-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid and its disodium salt, process for their preparation and their use Download PDFInfo
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- 0 C*(c(C(C(c1c-2[n]c(C([*-])=O)c1)=N)=O)c-2c(C(O*)=O)c1)c1C(O*)=O Chemical compound C*(c(C(C(c1c-2[n]c(C([*-])=O)c1)=N)=O)c-2c(C(O*)=O)c1)c1C(O*)=O 0.000 description 2
- WSAORPUPGOUQIP-UHFFFAOYSA-N CCC(C(C(N)=C)=O)=O Chemical compound CCC(C(C(N)=C)=O)=O WSAORPUPGOUQIP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present disclosure is in the field of pharmaceutical and chemical sciences.
- the present disclosure relates to polymorphic form of pyrroloquinoline quinone (PQQ) and/or its salts represented by formula I
- R3 is Na + .
- the present disclosure also relates to a process for preparing polymorphic form of
- Pyrroloquinoline quinone is a natural product and is categorized as an essential
- PQQ is also known as methoxatin.
- primary uses of PQQ are to protect mitochondria from oxidative stress, providing neuroprotection and cardioprotection.
- Common food sources of PQQ are parsley, green pepper, green tea, papaya, kiwi, milk and tofu.
- the available concentrations of PQQ in the food sources are only in picomolar (pM) to nanomolar (nM) levels. This necessitates the development of chemical processes which can produce large quantities of PQQ and its salts.
- Polymorphism is the ability of a chemical/pharmaceutical compound in the solid state to exist in different crystalline forms having the same chemical composition with modified physical properties and varied biological applications. Identification of new polymorphic forms of therapeutically important chemical molecules is an important step in the drug development process.
- Junichi EDAHIRO et al (US 201201 16087 A I) reported the defined crystal structure of PQQ di and tri sodium salts.
- the final isolation involved usage of organic solvents.
- alcoholic solvents are known to form adducts with PQQ.
- Figure 1 illustrates the powder XRD spectra of polymorph- 1 (Form 1 ) of PQQ.
- Figure 2 illustrates the powder XRD spectra of polymorph-2 (Form2) of PQQ.
- Figure 3 illustrates the powder XRD spectra of polymorph- 3 (Form 3) of PQQ salt.
- Figure 4 illustrates the powder XRD spectra of polymorph-4 (Form 4) of PQQ salt.
- Figure 5 illustrates the powder XRD spectra of polymorph- 5 (Form 5) of PQQ salt.
- Figure 6 illustxates the powder XRD spectra of polymorph-6 (Form 6) of PQQ salt.
- Figure 7 illustrates the powder XRD spectra of polymorph-? (Form 7) of PQQ salt. STATEMENT OF THE DISCLOSURE
- R3 is Na + , wherein said process comprises step of reacting Formula 111 with base followed by acid treatment to obtain the compound of Formula I
- R2 is selected from a group comprising hydrogen, straight or branched chain CI -8 alkyl, straight or branched chain C I -8 alkenyl, straight or branched chain Cl -8 alkynyl , aralkyl, substituted aralkyl, heteroaralkyl and substituted heteroaralkyl, and wherein each of the substituent is optionally substituted; and a composition comprising a polymorphic form of PQQ or its salt represented by formula I:
- the polymorphic form of PQQ is selected from a group comprising Form 1 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2 ⁇ of 7.9447 ⁇ 0.2 °, 1 1.7552 ⁇ 0.2 °, 12.6559 ⁇ 0.2 °, 14.8219 ⁇ 0.2 °, 16.0264 ⁇ 0.2 °, 17.0684 ⁇ 0.2 °, 18.8257 ⁇ 0.2 °, 19.5474 ⁇ 0.2 °, 22.5303 ⁇ 0.2 °, 23.5594 ⁇ 0.2 °, 24.7954 ⁇ 0.2 °, 25.6632 ⁇ 0.2 °, 27.13 ⁇ 0.2 °, 28.3092 ⁇ 0.2 °, 29.1776 ⁇ 0.2 °, 30.2626 ⁇ 0.2 °, 31.923 ⁇ 0.2 °, 34.6208 ⁇ 0.2 °, 35.7228 ⁇
- the polymorphic form of salt of compound represented by Formula II is a disodium salt.
- the polymorphic form of PQQ salt is selected from a group comprising Form 3 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2 ⁇ of 8.3367 ⁇ 0.2 °, 9.5883 ⁇ 0.2 °, 12.2471 ⁇ 0.2 °, 15.2353 ⁇ 0.2 °, 16.6527 ⁇ 0.2 °, 20.989 ⁇ 0.2 °, 22.7837 ⁇ 0.2 °, 26.0084 ⁇ 0.2 °, 27.4215 ⁇ 0.2 °, 29.174 ⁇ 0.2 °, 34.4201 ⁇ 0.2 °, 38.7959 ⁇ 0.2 °, Form 4 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2 ⁇ of 6.2526
- the polymorphic form of PQQ salt is selected from a group comprismg Form 3, Form 4, Form 5 Form 6 and Form 7.
- the Form 3 has X-ray powder diffractogram with the characteristic peaks shown in Figure 3
- the Form 4 has X- ray powder diffractogram with the characteristic peaks shown in Figure 4
- the Form 5 has X-ray powder diffractogram with the characteristic peaks shown in Figure 5
- Form 6 has X-ray powder diffractogram with the characteristic peaks shown in Figure 6
- the Form 7 has X-ray powder diffractogram with the characteristic peaks shown in Figure 7
- the present disclosure further relates to a process for the preparation of a polymorphic form of PQQ or its salt represented by formula I:
- R3 is Na + , wherein said process comprises step of reacting Formula III with base followed by acid treatment to obtain the compound of Formula I
- R2 is selected from a group comprising hydrogen, straight or branched chain CI -8 alkyl, straight or branched chain CI -8 alkenyl, straight or branched chain CI -8 aikynyl, aralkyl, substituted aralkyl, heteroaralkyl and substituted heteroaralkyl, and wherein each of the substituent is optionally substituted.
- the above process is carried out in presence of base either sodium hydroxide or sodium carbonate.
- the above process is carried out in presence of acid either hydrochloric acid or sulphuric acid.
- the above process is carried out at a temperature ranging from about 10 °C to about 80 °C» and for a time period ranging from about one hour to about 18 hours.
- the above process further comprises isolation and/or purification of the obtained pol PPQ or its salts.
- the said isolation comprises acts selected from a group comprising, addition of solvent, quenching, filtration, and extraction and combination of acts in any order thereof.
- the present disclosure further relates to a composition
- a composition comprising a polymorphic form of PQQ or its salt represented by formula I:
- R3 is Na + , optionally along with excipients.
- the composition is a iiutraceutical composition or a pharmaceutical composition; and wherein the excipient is selected from a group comprising binder, disintegrant, diluent, lubricant, plasticizer, permeation enhancer and solubilizer, or any combination thereof.
- the composition is formulated into dosage form selected from a group comprising tablet, troches, lozenges, aqueous or oily suspensions, ointment, patch, gel, lotion, dentifrice, capsule, emulsion, creams, spray, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, elixirs and food supplement, or any combination thereof.
- the present disclosure further relates to the use of a polymorphic form of PQQ and/or its salt represented by formula I:
- the precipitate is filtered to obtain product
- the precipitate is filtered at 0-5°C to obtain the product [4,5-Dioxo-4,5-dihydro-lH-pyrroio[2,3-f
- the solid was dried at 25-30 °C over a period of 24h under reduced pressure to attain water content is about 22%. (about 0.90 Kg, Yield: 90%).
- the product obtained in example 4 was further dried at 25-30 °C to attain moisture content about 12%.
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Abstract
The present disclosure relates to polymorphic form of PQQ and/or its salts represented by formula (I), wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" = 0 and (b) "n" = 1, "m" = 2; and; R3 is Na+. The present disclosure also relates to a process for preparing the polymorphic form of compound of formula (I) and/or its salts, a composition comprising the polymorphic form of compound of formula (I) and/or its salts and use thereof.
Description
POLYMORPHIC FORMS OF 4,5-DIHYDRO-1 H-PYRROLO[2,3-F]QUINOLINE-2,7,9-TRICARBOXYLIC ACID AND ITS DISODIUM SALT, PROCESS FOR THEIR PREPARATION AND THEIR USE
5 TECHNICAL FIELD
The present disclosure is in the field of pharmaceutical and chemical sciences. The present disclosure relates to polymorphic form of pyrroloquinoline quinone (PQQ) and/or its salts represented by formula I
10 Formula I
wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3 , "m" = 0 and (h)
"n" = 1, "m" = 2; and
R3 is Na+.
15 The present disclosure also relates to a process for preparing polymorphic form of
compounds of formula I, a composition comprising polymorphic form of compounds of formula 1 and use thereof.
BACKGROUND AND PRIOR ART
Pyrroloquinoline quinone (PQQ) is a natural product and is categorized as an essential
20 micronutrient and dietary supplement as it plays a critical role in the mitochondrial
biogenesis. PQQ is also known as methoxatin. Among many applications, primary uses of
PQQ are to protect mitochondria from oxidative stress, providing neuroprotection and cardioprotection. Common food sources of PQQ are parsley, green pepper, green tea, papaya, kiwi, milk and tofu. However, the available concentrations of PQQ in the food sources are only in picomolar (pM) to nanomolar (nM) levels. This necessitates the development of chemical processes which can produce large quantities of PQQ and its salts.
Few reports are known (J. Am. Chem. Soc. 103 (1981), 5599 -5600; He!v, Chem, Acta 76 (1993), 1667; WO2QQ6/102642A1 , IP 7413024 A) in literature to produce PQQ by chemical method as a free acid and its salts. However, the synthesis involves large number (9-10) of steps and the isolation of advanced intermediates and final product further involves tedious workup procedure.
Several research groups have reported different polymorphs of PQQ with or without metal salts and process for preparation of PQQ polymorphs. Polymorphism is the ability of a chemical/pharmaceutical compound in the solid state to exist in different crystalline forms having the same chemical composition with modified physical properties and varied biological applications. Identification of new polymorphic forms of therapeutically important chemical molecules is an important step in the drug development process.
Recently, Junichi EDAHIRO et al (US 201201 16087 A I) reported the defined crystal structure of PQQ di and tri sodium salts. However, the final isolation involved usage of organic solvents. Furthermore, alcoholic solvents are known to form adducts with PQQ.
Hence, it can be observed that there is an immense need for better and simpler synthetic routes for obtaining Pyrroioquinoline quinone (PQQ) salts. The present disclosure aims at overcoming the drawbacks of prior art and provide with stable crystalline forms of PQQ and its salts by improved, cost effective and scalable synthetic routes having minimal steps from advance intermediate.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS:
The features of the present disclosure will become more fully apparent from the following description taken in conjunction with the accompanying drawings. Understanding the drawings depict only several embodiments in accordance with the disclosure and are therefore, not to be considered limiting of its scope, the disclosure will be described with additional specificity and detail through use of the accompanying drawings:
Figure 1 illustrates the powder XRD spectra of polymorph- 1 (Form 1 ) of PQQ.
Figure 2 illustrates the powder XRD spectra of polymorph-2 (Form2) of PQQ.
Figure 3 illustrates the powder XRD spectra of polymorph- 3 (Form 3) of PQQ salt. Figure 4 illustrates the powder XRD spectra of polymorph-4 (Form 4) of PQQ salt.
Figure 5 illustrates the powder XRD spectra of polymorph- 5 (Form 5) of PQQ salt.
Figure 6 illustxates the powder XRD spectra of polymorph-6 (Form 6) of PQQ salt.
Figure 7 illustrates the powder XRD spectra of polymorph-? (Form 7) of PQQ salt. STATEMENT OF THE DISCLOSURE
Accordingly, the present disclosure relates to a polymorphic form of PQQ or its salt represented by formula I:
Formula I
wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" :=: 0 and (b) "n" = 1 , "m" = 2, and 3 is Na ; a process for the preparation of a polymorphic form of PQQ or its salt represented by formula I:
Formula I wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" = 0 and (b) "n" = 1 , "m" :=: 2, and
R3 is Na+, wherein said process comprises step of reacting Formula 111 with base followed by acid treatment to obtain the compound of Formula I
Formula III
wherein, R2 is selected from a group comprising hydrogen, straight or branched chain CI -8 alkyl, straight or branched chain C I -8 alkenyl, straight or branched chain Cl -8 alkynyl , aralkyl, substituted aralkyl, heteroaralkyl and substituted heteroaralkyl, and wherein each of the substituent is optionally substituted; and a
composition comprising a polymorphic form of PQQ or its salt represented by formula I:
Formula I wherein "n" and "m" are selected from a group consisting of; (a) "n" = 3, "m" = 0 and (b) "n" = 1 , "m" = 2, and optionally along with excipients.
DETAILED DESCRIPTION OF THE DISCLOSURE
Accordingly, the present disclosure relates to a polymorphic form of PQQ or its salt represented by formula I:
Formula 1
wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" :=: 0 and (b) "n" = 1 , "m" = 2; and 3 is Na .
In an embodiment of the present disclosure, when n=3 and m=0, the polymorphic form of PQQ is selected from a group comprising Form 1 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 7.9447 ± 0.2 °, 1 1.7552 ± 0.2 °, 12.6559 ± 0.2 °, 14.8219 ± 0.2 °, 16.0264 ± 0.2 °, 17.0684 ± 0.2 °, 18.8257 ± 0.2 °, 19.5474 ± 0.2 °, 22.5303 ± 0.2 °, 23.5594 ± 0.2 °, 24.7954 ± 0.2 °, 25.6632 ± 0.2 °, 27.13 ± 0.2 °, 28.3092 ± 0.2 °, 29.1776 ± 0.2 °, 30.2626 ± 0.2 °, 31.923 ± 0.2 °, 34.6208 ± 0.2 °, 35.7228 ± 0.2 °, 37.0506 ± 0.2 °, 37.8323 ± 0.2 °, 38.8985 ± 0.2 °, 39.6034 ± 0.2 °, 40.9434 ± 0.2 °, 43.9407 ± 0.2 °, 48.3058 ± 0.2 °, 54.7932 ± 0.2 °, 58.641 1 ± 0.2 °and Form 2 with X-ray- powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 12.5376 ± 0.2 °, 14.1 135 ± 0.2 °, 15.3635 ± 0.2 °, 16.6934 ± 0.2 °, 18.0525 ± 0.2 °, 22.3898 ± 0.2 °, 25.085 ± 0.2 °, 28.2059 ± 0.2 °, 31.2156 ± 0.2 °, 35.8287 ± 0.2 °, 37.3867 ± 0.2 °, 39.5429 ± 0.2 °, 42.936 ± 0.2 °, 58.4641 ± 0.2 °.
In another embodiment of the present disclosure, the polymorphic form of salt of compound represented by Formula II is a disodium salt.
Formula II
wherein "n:=:l " and "m:=:2"; wherein, R3 is Na+.
In yet another embodiment of the present disclosure, when n= 1 , m=2, and R3 is Na+, the polymorphic form of PQQ salt is selected from a group comprising Form 3 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 8.3367 ± 0.2 °, 9.5883 ± 0.2 °, 12.2471 ± 0.2 °, 15.2353 ± 0.2 °, 16.6527 ± 0.2 °, 20.989 ± 0.2 °, 22.7837 ± 0.2 °, 26.0084 ± 0.2 °, 27.4215 ± 0.2 °, 29.174 ± 0.2 °, 34.4201 ± 0.2 °, 38.7959 ± 0.2 °, Form 4 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 6.2526 ± 0.2 °, 8.09 ± 0.2 °, 8.5645 ± 0.2 °, 14.0915 ± 0.2 °, 17.569 ± 0.2 °, 18.6382 ± 0.2 °, 22.2638 ± 0.2 °, 23.0319 ± 0.2 °, 23.9335 ± 0.2 °, 26.4089 ± 0.2 °, 27.2276 ± 0.2 °, 28.2427 ± 0.2 °, 29.5534 ± 0.2 °, 31.7176 ± 0.2 °, 33.751 1 ± 0.2 °, 34.7226 ± 0.2 °, 36.9752 ± 0.2 °, 38.8203 ± 0.2 °, 40.9029 ± 0.2 °, 43.1906 ± 0.2 °, 45.3693 ± 0.2 °, 47.3751 ± 0.2 °, Form 5 with X-ray powder dirrractogram pattern having characteristic peaks at diffraction angles 2Θ of 6.3087 ± 0.2 °, 8.787 ± 0.2 °, 9.4638 ± 0.2 °, 11.1383 ± 0.2 °, 12.8604 ± 0.2 °, 14.0298 ± 0.2 °, 15.1081 ± 0.2 °, 17.032 ± 0.2 °, 21.1969 ± 0.2 °, 22.3969 ± 0.2 °, 23.3678 ± 0.2 °, 26.8503 ± 0.2 °, 27.6689 ± 0.2 °, 29.435 ± 0.2 °, 31.5489 ± 0.2 °, 32.2817 ± 0.2 °, 34.0255 ± 0.2 °, 36.884 ± 0.2 °, 38.6941 ± 0.2 °, 43.2067 ± 0.2 °, 45.2776 ± 0.2 °, Form 6 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 20 of 8.1 86 ± 0.2 °, 9.4246 ± 0.2 °, 18.5305 ± 0.2 °, 26.6158 ± 0.2 °, 27.292 ± 0.2 °, 31 .6378 ± 0.2 °, 45.4109 ± 0.2 °, 56.4274 ± 0.2 °, 66.181 1 ± 0.2 ° and Form 7 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 9.3426 ± 0.2 °, 1 1.6809 ± 0.2 °, 13.6028 ± 0.2 °, 14.9981 ± 0.2 °, 16.0269 ± 0.2 °, 1 8.9222 ± 0.2 °, 20.4534 ± 0.2 °, 22.0677 ± 0.2 °, 23.71 1 3 ± 0.2 °, 25.6284 ± 0.2 °, 26.4555 ± 0.2 °, 27.4617 ± 0.2 °, 28.5023 ± 0.2 °, 30.7997 ± 0.2 °, 31.6466 ± 0.2 °, 32.4609 ± 0.2 °, 35.9051 ± 0.2 °, 36.7705 ± 0.2 °, 38.0082 ± 0.2 °, 38.7336 ± 0.2 °, 41.5928 ± 0.2 °, 43.7879 ± 0.2 °, 45.3967 ± 0.2 °, 46.9161 ± 0.2 °, 48.9136 ± 0.2 °, 52.7775 ± 0.2 °, 56.5143 ± 0.2 °, 61.0903 ± 0.2 °, 66.189 ± 0.2 °.
In still another embodiment of the present disclosure, wherein the Form 1 has X-ray powder diffractogram with the characteristic peaks shown in Figure 1 and the Form 2 has X-ray powder diffractogram with the characteristic peaks shown in Figure 2.
In still another embodiment of the present disclosure, wherein when n=l , m=2 and R3 is Na", the polymorphic form of PQQ salt is selected from a group comprismg Form 3, Form 4, Form 5 Form 6 and Form 7.
In still another embodiment of the present disclosure, wherein the Form 3 has X-ray powder diffractogram with the characteristic peaks shown in Figure 3, the Form 4 has X- ray powder diffractogram with the characteristic peaks shown in Figure 4, the Form 5 has X-ray powder diffractogram with the characteristic peaks shown in Figure 5, Form 6 has X-ray powder diffractogram with the characteristic peaks shown in Figure 6 and the Form 7 has X-ray powder diffractogram with the characteristic peaks shown in Figure 7,
The present disclosure further relates to a process for the preparation of a polymorphic form of PQQ or its salt represented by formula I:
Formula I wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" = 0 and (b) "n" = 1 , "m" = 2; and
R3 is Na+, wherein said process comprises step of reacting Formula III with base followed by acid treatment to obtain the compound of Formula I
Formula III
wherein, R2 is selected from a group comprising hydrogen, straight or branched chain CI -8 alkyl, straight or branched chain CI -8 alkenyl, straight or branched chain CI -8 aikynyl, aralkyl, substituted aralkyl, heteroaralkyl and substituted heteroaralkyl, and wherein each of the substituent is optionally substituted.
In an embodiment of the present disclosure, the above process is carried out in presence of base either sodium hydroxide or sodium carbonate.
In another embodiment of the present disclosure, the above process is carried out in presence of acid either hydrochloric acid or sulphuric acid.
In yet another embodiment of the present disclosure, the above process is carried out at a temperature ranging from about 10 °C to about 80 °C» and for a time period ranging from about one hour to about 18 hours.
In still another embodiment of the present disclosure, the above process further comprises isolation and/or purification of the obtained pol PPQ or its salts. Further, the said isolation comprises acts selected from a group comprising, addition of solvent, quenching, filtration, and extraction and combination of acts in any order thereof.
The present disclosure further relates to a composition comprising a polymorphic form of PQQ or its salt represented by formula I:
Formula I
wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" :=: 0 and (b) "n" = 1, "m" = 2; and
R3 is Na+, optionally along with excipients.
In an embodiment of the present disclosure, the composition is a iiutraceutical composition or a pharmaceutical composition; and wherein the excipient is selected from a group comprising binder, disintegrant, diluent, lubricant, plasticizer, permeation enhancer and solubilizer, or any combination thereof.
In another embodiment of the present disclosure, the composition is formulated into dosage form selected from a group comprising tablet, troches, lozenges, aqueous or oily suspensions, ointment, patch, gel, lotion, dentifrice, capsule, emulsion, creams, spray, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, elixirs and food supplement, or any combination thereof.
The present disclosure further relates to the use of a polymorphic form of PQQ and/or its salt represented by formula I:
Formula I wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" = 0 and (b) "n" = 1 , "m" = 2; and R3 is Na"; for management of condition selected from a group comprising neuronal disorders, cardiovascular disorders and nutritional disorder and combinations thereof.
MATERIALS AND METHODS:
Chemicals were obtained from multiple commercial suppliers such as Apollo Scientific, Sigma-Aldrich and etc. Final purifications were carried out using Merck silica gel 230-400 mesh. TLC experiments were performed on alumina-backed silica gel 40 F254 plates (Merck, Darmstadt, Germany). The plates were illuminated under UV (254 nm) and KMn04. Melting points were determined using Buchi B-540 and are uncorrected. All JH NMR spectra were recorded on a Broker AM-300 (300 MHz for lH NMR), Broker BioSpin Corp., Germany. Molecular weights of unknown compounds were checked by LCMS 6200 series Agilent Technology. Chemical shifts are reported in ppm (δ) with reference to internal standard TMS. The signals are designated as follows: s, singlet; d, doublet; t, triplet; m, muitipiet; brs, broad singlet.
The chemicals employed follows;
1) 4,5-dioxo-4,5-dihydro-iFl-pyrrolo[2,3-fjquinoline-2,7,9-tricarboxyiic acid trimethyl ester
2) Sodium hydroxide
3) Sodium carbonate
4) Hydrochloric acid
5) Water
6) Methanol
7) Ethanol
Additional embodiments and features of the present disclosure will be apparent to one of ordinary skill in art based upon description provided herein. However, the following examples should not be construed to limit the scope of the present disclosure.
Example 1 : ynthesis ot 4,5~0ioxo-4,5~dil )vrro]oJ2,3-f1quinoline-2,7,9-tricarboxylic acid polymorph - Form 1 [Formula I, 'η' = 3 and im-
To about 35L of about 3.5% solution of sodium hydroxide, 4,5-dioxo-4,5-dihydro-l H- pyrrolo[2,3-f]quinolme-2,7,9-tricarboxy]ic acid trimethyl ester (1.0 kg,l eq, 2.686 moles) is added at about 25-30°C, The reaction mixture is stirred at about 25 °C to about 30 °C over a period of about 3 hours. Completion of reaction is monitored by HPLC. Thereafter, the reaction mixture is acidified (pH: <1) with 12N hydrochloric acid and stirred at 40-60 °C over a period of 12 hours to precipitate the reaction mass. The precipitate is filtered to obtain product | ,5-Dioxo-4,5-dihydro-lH-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid] as a bright red solid (about 0.80 Kg, Yield; 90%).
Purity by HPLC: 99.3 %
(DMSO, 300 MHz): 7.20 (s, ! H), 8.60 (s, 1 H) and 13.60 (bs, 3H)
(ATR, cnT) v: 3553, 3257, 3009, 2615, 1746, 171 1, 1644, 1506, 1399, 1197 and 767
Powder XRD spectra of polymorph- 1 of PQQ (Form 1);
The powder XRD spectra pattern of the polymorph 1 of PQQ (Form 1) is provided in Figure 1.
Peak List of polymorph 1 of PQQ (Form 1)
Example 2:
Synthesis of 4,5-Dioxo-4,5-dihvdro-lH-Dyrroioi2,3-f|qi8iijoIisie-2 ,7,9-tricarboxylic acid polymorph - Form 2 Formula I, = 3 a&d 'in' = 01
Purity by HPLC: 99.3 % *H NMR (DMSO, 300 MHz): 7.02 (s, 1H), 8.60 (s, 1H) and 13.60 (hs, 3H)
IR (ATR, cm"1) v: 3503, 3255, 2965, 1746, 1711, 1644, 1506, 1320, 1196 and 766 Powder XRD spectra of polymorph-2 of PQQ (Form 2):
The powder XRD spectra pattern of the polymorph 2 of PQQ (Form 2) is provided in Figure 2. Peak List of polymorph-2 of PQQ (Form 2)
Pos.[°2Th.] Height[cts] FWHM[°2Th.] d-spacing[A] Rel.Int[%]
12.5376 89.27 0.4723 7.06033 12.04
14.1 135 66.97 0.3936 6.27531 9.03
15.3635 52.59 0.5510 5.76742 7.09
16.6934 25.35 0.4723 5.31085 3.42
18.0525 75.28 0.6298 4.91397 10.15
22.3898 74.80 0.3936 3.97089 10.08
25.0850 12.67 0.9446 3.55002 1.71
* 28.2059 741.73 0.3936 3.16393 100.00
31.2156 12.29 0.4723 2.86539 1.66
35.8287 23.53 0.5510 2.50634 3.17
37.3867 33.07 0.4723 2.40540 4.46
* 39.5429 13.01 0.7085 2.27906 1.75
42.9360 11.31 0.6298 2.10649 1.52
58.4641 10.21 0.7680 1 .57736 1.38
Example 3:
Synthesis of 4,5-Dioxo-4,5-dihvdro-lH-pyrrolo[2,3-f|quinoline-2,7,9-tricarboxyUc acid disodium (PQQ.2Na) polymorph - Form 3 fFormnia II, "n" = 1, V = 21
Procedure;
To 15L of 30% solution sodium carbonate, 4,5-dioxo-4,5-dihydro-lH-pyrrolo[2,3- f]quinoline-2,7,9-tricarboxylic acid trimethyl ester ( 1.0 kg,l eq, 2.686 moles) is added at 25-30 °C. The reaction mixture is heated to 70°C to 75°C over a period of 16 hours. Completion of reaction is monitored by HPLC. Thereafter, the reaction mixture is acidified (pH: 3.0-3.5) with IN hydrochloric acid to precipitate the reaction mass. The precipitate is filtered at 0-5°C to obtain the product [4?5-Dioxo-4,5-dihydro- lH-pyrrolo[2,3-f]quinoline- 2,7,9-tricarboxylic acid disodium] as dark red solid (about 0.85 Kg, Yield: 85%).
>, 3ί e): 6.84 (s, 1H), 8.48 (s, 1H); LC-MS (ESI): 329 (M-H), Purity by HPLC: 98.6%
~l) v 3407, 1719, 1666, 1621 , 1580, 1537, 1497, 1356, 1243, 975 and 731
The powder XRD spectra pattern of the polymorph 3 (Form 3) of the PQQ salt is provided in Figure 3.
Peak List of Polymorph- 3 of PQQ salt (Form 3)
Example 4:
Sy thesis of 4,5-Dioxo-4,5-dihvdro-.tH-pyrrolof2,3-f|quinoUne-2,7,9-tricarboxylic acid disodium (PQQ.2Na) polymorph - Form 4 [Formula II, "n" = 1, V = 21
Procedure: To 15L of 30% solution sodium carbonate, 4,5-dioxo-4,5-dihydro-lH-pyrrolo[2,3- f]quinoline-2,7,9-tricarboxylic acid trimethyl ester ( 1.0 kg,. I eq, 2.686 moles) is added at 25-30 °C. The reaction mixture is heated to 70°C to 75°C over a period of 16 hours. Completion of reaction is monitored by HPLC. Thereafter, the reaction mixture is acidified (pH: 3.0-3.5) with 12 hydrochloric acid to precipitate the reaction mass. The precipitate is filtered at 0-5°C to obtain the product [4,5-Dioxo-4,5-dihydro-lH-pyrroio[2,3-f|quinoline-
2,7,9-tricarboxylic acid disodium] as dark red solid. The solid was dried at 25-30 °C over a period of 24h under reduced pressure to attain water content is about 22%. (about 0.90 Kg, Yield: 90%).
1H NMR (D20, 300 MHz): 7.07 (s, 1H), 7.69 (s, 1H); LC-MS (ESI): 329 (M-H), Ferity by HPLC: 99.5%
IR (ATR, cm"1) v: 3500, 1669, 1619, 1540, 1496, 1356, 1241, and 728 Powder XRD spectra of Polymorph -4 of PQQ salt (Form 4):
The powder XRD spectra pattern of the polymorph 4 of PQQ salt is provided in Figure 4. Peak List of Polvmorph-4 (Form 4)
Peak List
Pos.f°2Th.l Heifihtfcts] FWHM[°2Th.] d-spacing[A] Rel.Int.f%l
6.2526 54.03 0.4723 14.13589 35.63
8.09 96.43 0.3149 10.92909 63.59
8.5645 84.08 0.4723 10.32463 55.45
14.0915 61.1 0.3149 6.28507 40.29
17.569 17.93 0.3149 5.04809 1 1.83
18.6382 33.79 0.4723 4.76085 22.28
22.2638 17.22 0.4723 3.99309 1 1.36
23.0319 17.83 0.3149 3.86163 1 1.76
23.9335 19.32 0.3149 3.71815 12.74
26.4089 126.44 0.3149 3.37499 83.38
27.2276 151.64 0.4723 3.27533 100
28.2427 89.84 0.4723 3.15988 59.25
29.5534 62,19 0.3936 3.02266 41.01
31.7176 26.43 0.9446 2.82118 17.43
33.751 1 34.13 0.3149 2.65571 22.51
34.7226 22.18 0.3149 2.5836 14.63
36.9752 22,96 0.6298 2,43121 15.14
38.8203 33.18 0.3149 2.3198 21.88
40.9029 28.27 0.3149 2.20638 18.64
43.1906 20.23 0.4723 2.09466 13.34
45.3693 6.97 0.4723 1.99901 4.6
47.3751 17.14 0.576 1.91737 1 1.3
ayoisiesss ot 4,5~0ioxo-4,5~dil jvrro]oi2,3-fl uiiio!io.e~2 ,7,9~t5*icarboxYlic atic
The product obtained in example 4, was further dried at 25-30 °C to attain moisture content about 12%.
The below spectral data con'esponds to PQO with 12% moisture content.
Note: When water content is 12%, there is a new peak appeared at 2Θ of 1 1.139.
1H NMR (D20, 300 MHz): 6,97 (s, IH), 8.48 (s, IH); LC-MS (ESI): 329 (M-H), Purity by HPLC: 99.5%
IR (ATR, cm"1) v: 3500, 3408, 1669, 1621 , 1497, 1359, 1241 and 729 Example 6: 4,5-Dioxo-4,5-dihvdro-lH-pyrrolo[2.i3-flquinoline-2.i7,9-tricarboxylic acid disodium
(PQQ.2Na) polymorph - Form 6 [Formula II, "n" = 1 , "m" = 2)
¾ NMR (D20, 300 MHz): 6.84 (s, IH), 8.48 (s, IH); LC-MS (ESI): 329 (M-H), Purity by HPLC: 99.4 %
IR (ATR, cm"1) v: 3423, 2558, 1717, 1674, 161 1 , 1543, 1502, 1235, 1 147, 938 and 718 Powder XRD spectra of polymorph-5 of PQQ salt (Form 6):
The powder XRD spectra pattern of the polymorph 6 is provided in Figure 6.
Peak List of polymorph-6:
To 15L of 3.5 % solution of sodium hydroxide, 4,5-dioxo-4,5-dihydro-l H-pyrrolo[2,3- f]quinoline-2,7,9-tricarboxylic acid trimethyl ester (1 .0 kg,l eq, 2.686 moles) is added at 25~30°C. The reaction mixture was heated to 25 to 30 °C over a period of 16 h Completion of reaction is raonitored by HPLC. Thereafter, the reaction mixture is acidified (pH: 3.0- 3.5) with 12N hydrochloric acid over a period of 3h under vigorous stirring to precipitate the reaction mass. The precipitate is filtered at 0-5 °C to obtain product 4,5-Dioxo-4,5- dihydro- lH-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid disodium] as dark red solid (about 0.88 Kg, 88%).
1H NMR (D20, 300 MHz): 6,84 (s, IH), 8.48 (s, IH); LC-MS (ESI): 329 (M-H), Purity by HPLC: 99.4 %
1R (ATR, cm-1) v: 3414, 2474, 1681, 1643, 1503, 1356, 1296, 1238, 1084, 1049, 81 1, 723 and 698
Powder XRD spectra of polymorph-6 of PQQ salt (Form 7):
The powder XRD spectra pattern of the polymorph 7 is provided in Figure 7.
Peak List of polymorph-?
Pos.i°2Th.l Heiehtictsl FWHMi°2Th.l d-spacingfA] ReLInt.1%]
9.3426 251.02 0.4723 9.46644 76.02
11.6809 15.80 0.4723 7.5761 1 4.78
13.6028 41.1 1 0.3Ϊ49 6.50976 12.45
14.9981 77.18 0.3149 5.90713 23.37
16.0269 72.44 0.4723 5.5301 7 21.94
18.9222 38.41 0.3149 4.69003 11.63
20.4134 46.95 0.4723 4.35067 14', 2-2
22.0677 52.94 0.3149 4.02812 16.03
23.75 53 50.53 0.4723 3.75250 15.30
25.6284 20.91 0.3149 3.47597 6.33
26.4555 63.79 0.3149 3.36915 19.32
27.4617 330.21 0.3149 3.24795 100.00
28.5023 157.52 0.3149 3.13169 47.70
30.7997 32.81 0.3149 2.90313 9.94
31.6466 0.3149 2.82735 69.09
32.4609 14.74 0.3936 2.75826 4.46
35.9051 57.91 0.3149 2.501 18 17.54
36.7705 20.77 0.3936 2.44428 6.29
38.0082 46.45 0.3149 2.36748 14.07
38.7336 33.15 0.3936 2.32480 10.04
41.5928 15.95 0.6298 2.17136 4.83
43.7879 9.27 0.7872 2.06747 2.81
45.3967 126.11 0.4723 1.99787 38.19
46.9161 18.71 0.7872 1.93665 5.67
48.9136 9.44 0.4723 1.86214 2.86
52.7775 7.94 0.4723 1.73455 2.41
56.5143 35.19 0.4723 1.62841 10.66
61.0903 3.33 0.9446 5.51694 1.01
66.1890 13.72 0.3840 1.41075 4.15
Claims
We Claim,
1 , A polymorphic form of PQQ or its salt represented by formula I:
wherein "n" and "m" are selected from a group consisting of: (a) "n" := 3, "m" = 0
R3 is Nal.
2. The polymorphic form as claimed in claim i, wherein when n=3 and m=0, the polymorphic form of PQQ is selected from a group comprising Form 1 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 7,9447 ± 0.2 °, 11.7552 ± 0.2 °, 12.6559 ± 0.2 °, 14.8219 ± 0.2 °, 16.0264 ± 0.2 °, 17.0684 ± 0.2 °, 18.8257 ± 0.2 °, 19.5474 ± 0.2 °, 22.5303 ± 0.2 °, 23.5594 ± 0.2 °, 24.7954 ± 0.2 °, 25.6632 ± 0.2 °, 27.13 ± 0.2 °, 28.3092 ± 0.2 °, 29.1776 ± 0.2 °, 30.2626 ± 0.2 °, 31.923 ± 0.2 °, 34.6208 ± 0.2 °, 35.7228 ± 0.2 °, 37.0506 ± 0.2 °, 37.8323 ± 0.2 °, 38.8985 ± 0.2 °, 39.6034 ± 0.2 °, 40.9434 ± 0.2 °, 43.9407 ± 0.2 °, 48.3058 ± 0.2 °, 54.7932 ± 0.2 °, 58.6411 ± 0.2 °and Form 2 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 12.5376 ± 0.2 °, 14.1135 ± 0.2 °, 15.3635 ± 0.2 °, 16.6934 ± 0.2 °, 18.0525 ± 0.2 °, 22.3898 ± 0.2 °, 25.085 ± 0.2 °, 28.2059 ± 0.2 °, 31.2156 ± 0.2 °, 35.8287 ± 0.2 °, 37.3867 ± 0.2 °, 39.5429 ± 0.2 °, 42.936 ± 0.2 °, 58.4641 ± 0.2 °.
3. The polymorphic form as claimed in claim 1, wherein when n=l, m . and R3 is Na+, the polymorphic form of PQQ salt is selected from a group comprising Form 3 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 8.3367 ± 0.2 °, 9.5883 ± 0.2 °, 12.2471 ± 0.2 °, 15.2353 ± 0.2 °, 16.6527 ± 0.2 °, 20.989 ± 0.2 °, 22.7837 ± 0.2 °, 26.0084 ± 0.2 °, 27.4215 ± 0.2 °, 29.174 ± 0.2 °, 34.4201 ± 0.2 °, 38.7959 ± 0.2 °, Form 4 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 6.2526 ± 0.2 °, 8.09 ± 0.2 °, 8.5645 ± 0.2 °, 14.0915 ± 0.2 °, 17.569 ± 0.2 °, 18.6382 ± 0.2 °, 22.2638 ± 0.2 °, 23.0319 ± 0.2 °, 23.9335 ± 0.2 °, 26.4089 ± 0.2 °, 27.2276 ± 0.2 °, 28.2427 ± 0.2 °, 29.5534 ± 0.2 °, 31.7176 ± 0.2 °, 33.7511 ± 0.2 °, 34.7226 ± 0.2 °, 36.9752 ± 0.2 °, 38.8203 ± 0.2 °, 40.9029 ± 0.2 °, 43.1906 ± 0.2 °, 45.3693 ± 0.2 °, 47.3751 ± 0.2 °, Form 5 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 6.3087 ± 0.2 °, 8.787 ± 0.2 °, 9.4638 ± 0.2 °, 1 1 .5383 ± 0.2 °, 12.8604 ± 0.2 °, 14.0298 ± 0.2 °, 15.1081 ± 0.2 °, 17.032 ± 0.2 °, 21.1969 ± 0.2 °, 22.3969 ± 0.2 °, 23.3678 ± 0.2 °, 26.8503 ± 0.2 °, 27.6689 ± 0.2 °, 29.435 ± 0.2 °, 31.1489 ± 0.2 °, 32.2817 ± 0.2 °, 34.0255 ± 0.2 °, 36.884 ± 0.2 °, 38.6941 ± 0.2 °, 43.2067 ± 0.2 °, 45.2776 ± 0.2 °, Form 6 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 8.386 ± 0.2 °, 9.4246 ± 0.2 °, 18.5305 ± 0.2 °, 26.6358 ± 0.2 °, 27.292 ± 0.2 °, 31.6378 ± 0.2 °, 45.4309 ± 0.2 °, 56.4274 ± 0.2 °, 66.1815 ± 0.2 ° and Form 7 with X-ray powder diffractogram pattern having characteristic peaks at diffraction angles 2Θ of 9.3426 ± 0.2 °, 11.6809 ± 0.2 °, 33.6028 ± 0.2 °, 14.9985 ± 0.2 °, 56.0269 ± 0.2 °, 18.9222 ± 0.2 °, 20.4534 ± 0.2 °, 22.0677 ± 0.2 °, 23.7113 ± 0.2 °, 25.6284 ± 0.2 °, 26.4555 ± 0.2 °, 27.4617 ± 0.2 °, 28.5023 ± 0.2 °, 30.7997 ± 0.2 °, 35.6466 ± 0.2 °, 32.4609 ± 0.2 °, 35.9055 ± 0.2 °, 36.7705 ± 0.2 °, 38.0082 ± 0.2 °, 38.7336 ± 0.2 °, 45.5928 ± 0.2 °, 43.7879 ± 0.2 °, 45.3967 ± 0.2 °, 46.9565 ± 0.2 °, 48.9136 ± 0.2 °, 52.7775 ± 0.2 °, 56.5143 ± 0.2 °, 61.0903 ± 0.2 °, 66.189 ± 0.2 °.
4. A process for the preparation of a polymorphic form of PQQ or its salt represented by formula I:
Formula I wherein "n" and "m" are selected from a group consisting of: (a) "n" = 3, "m" = 0 and (b) "n" = 1 , "m" = 2: and
wherein said process comprises step of reacting Formula III with base followed by acid treatment to obtain the compound of Formula I
Formula III
wherein, R2 is selected from a group comprising hydrogen, straight or branched chain CI -8 alkyl, straight or branched chain CI -8 alkenyl, straight or branched chain Cl-8 aikynyl, aralkyl, substituted araikyl, heteroaralkyi and substituted heteroaralkvl, and wherein each of the substituent is optionally substituted.
5. The process as claimed in claim 4, wherein the base is sodium hydroxide or sodium carbonate.
6. The process as claimed in claim 4, wherein the acid is hydrochloric acid or sulphuric acid.
7. The process as claimed in claim 4, wherein said process is carried out at a temperature ranging from about 10 °C to about 80 °C, and for a time period ranging from about one hour to about 18 hours.
8. A composition comprising a polymorphic form of PQQ or its salt represented by formula I;
Formula I wherein "n" and "m" are selected from a group consisting of; (a) "n" = 3, "m" = 0 and (b) "n" = 1, "m" = 2: and
3 is Na ,
optionally along with excipients.
9. The composition as claimed in claim 8, wherein the composition is a nutraceutica] composition or a pharmaceutical composition; and wherein the excipient is selected from a group comprising binder, disintegrant, diluent, lubricant, plasticizer, permeation enhancer and solubilizer, or any combination thereof.
10. The composition as claimed in claim 8, wherein the composition is formulated into dosage form selected from a group comprising tablet, troches, lozenges, aqueous or oily suspensions, ointment, patch, gel, lotion, dentifrice, capsule, emulsion, creams, spray, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, elixirs and food supplement, or any combination thereof.
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| CN201580019780.7A CN106255691A (en) | 2014-04-16 | 2015-04-15 | 4,5 dihydro 1H pyrrolo-[2,3 F] quinoline 2,7,9 tricarboxylic acids and the polymorphic forms of disodium salt, Preparation Method And The Uses |
| EP15721334.9A EP3131899A1 (en) | 2014-04-16 | 2015-04-15 | Polymorphic forms of 4,5-dihydro-1h-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid and its disodium salt, process for their preparation and their use |
| JP2016563108A JP2017513863A (en) | 2014-04-16 | 2015-04-15 | Polymorphic forms of 4,5-dihydro-1H-pyrrolo [2,3-F] quinoline-2,7,9-tricarboxylic acid and its disodium salt, methods for their preparation and their use |
| US15/302,720 US20170022200A1 (en) | 2014-04-16 | 2015-04-15 | Polymorphic forms of 4,5-dihydro-1h-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid and its disodium salt, process for their preparation and their use |
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| CN105218543A (en) * | 2015-11-02 | 2016-01-06 | 诸城市浩天药业有限公司 | Pyrroloquinoline quinone B crystal form and preparation method thereof |
| CN105315278A (en) * | 2015-11-02 | 2016-02-10 | 诸城市浩天药业有限公司 | PQQ (pyrroloquinoline quinone) A crystal form and preparation method thereof |
| US10364244B2 (en) * | 2015-09-25 | 2019-07-30 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof |
| CN112125899A (en) * | 2019-06-24 | 2020-12-25 | 浙江医药股份有限公司 | Pyrroloquinoline quinone disodium salt crystal, preparation method thereof and composition containing pyrroloquinoline quinone disodium salt crystal |
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| US20210267240A1 (en) * | 2018-08-30 | 2021-09-02 | Mitsubishi Gas Chemical Company, Inc. | Photodeterioration inhibitor, beverage comprising the same, and method for inhibiting photodeterioration |
| JP7301347B2 (en) * | 2019-05-22 | 2023-07-03 | 株式会社ブルーム・クラシック | Sirtuin 1 activator and skin cosmetic for sirtuin 1 activation |
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| US10364244B2 (en) * | 2015-09-25 | 2019-07-30 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof |
| CN105218543A (en) * | 2015-11-02 | 2016-01-06 | 诸城市浩天药业有限公司 | Pyrroloquinoline quinone B crystal form and preparation method thereof |
| CN105315278A (en) * | 2015-11-02 | 2016-02-10 | 诸城市浩天药业有限公司 | PQQ (pyrroloquinoline quinone) A crystal form and preparation method thereof |
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| JP2018533623A (en) * | 2015-11-02 | 2018-11-15 | ジュチェン ハウテン ファーム カンパニー リミテッドＺｈｕｃｈｅｎｇ Ｈａｏｔｉａｎ Ｐｈａｒｍ Ｃｏ．，Ｌｔｄ | Crystal form B of pyrroloquinoline quinone and process for producing it |
| US10562895B2 (en) | 2015-11-02 | 2020-02-18 | Zhucheng Haotian Pharm Co., Ltd. | Pyrroloquinoline quinone B crystal form and preparation method therefor |
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|---|---|
| EP3131899A1 (en) | 2017-02-22 |
| US20170022200A1 (en) | 2017-01-26 |
| MA39715A (en) | 2015-10-22 |
| CN106255691A (en) | 2016-12-21 |
| JP2017513863A (en) | 2017-06-01 |
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