KR860000450B1 - Process for the preparation of alpha-6-deoxy-5-hydroxy tetra cycline and sodium tetrametaphosphate complexes - Google Patents

Process for the preparation of alpha-6-deoxy-5-hydroxy tetra cycline and sodium tetrametaphosphate complexes Download PDF

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KR860000450B1
KR860000450B1 KR1019810004468A KR810004468A KR860000450B1 KR 860000450 B1 KR860000450 B1 KR 860000450B1 KR 1019810004468 A KR1019810004468 A KR 1019810004468A KR 810004468 A KR810004468 A KR 810004468A KR 860000450 B1 KR860000450 B1 KR 860000450B1
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Abstract

A water-soluble complexes of α-6-deoxy-5-hydroxytetracycline (I) and Na tetrametaphosphate was prepd. from I. Thus, fleshly prepd. 4.33g of (HPO3)n (n=4) was treated with 1 ml of H2O and 20g of I H2O and later with 0.574g of NaOH in MeOH. After adding iso-PrOH, the growing cryst. compd. was filtered, washed, dried to give 21g of I and Na (HPO3)n (n=4) complexes. The major advantage of using this complexes is its decreased interference in the action in human serum of natural bactericides. The bioavailability of this complexes (4.32 μ g/ml/3h) was higher than that of I capsules.

Description

α-6-데옥씨-5-하이드록씨 테트라 싸이클린과 소듐 테트라메타포스 페이트의 수용성 복합체의 제조방법Method for preparing a water-soluble complex of α-6-deoxy-5-hydroxy tetracycline and sodium tetrametaphosphate

본 발명은 α-6-데옥씨-5-하이드록씨 테트라싸이클린과 소듐 테트라 메타포스페이트의 새로운 수용성 복합체 및 저급알콜과 물로 이들을 솔베이트시키는 제조방법에 관한 것이다.The present invention relates to a novel water soluble complex of α-6-decoxy-5-hydroxy tetracycline and sodium tetra metaphosphate and a process for solvating them with lower alcohols and water.

이러한 새로운 유도체 즉 독씨사이클린테트라메타포스페이트 소듐 복합체는 독씨싸이클린 및 이미 알려진 이들의 염 및 복합체들과 연관시 현저한 장점을 보여주며, 오랜동안 항세균제로 알려졌던 테트라 싸이클린 복합체의 단점의 하나인 인간혈청(Humanserum)의 자연적 살균작용에 대한 불간섭성에 관한한 특히 그러하다.These new derivatives, the doxycycline tetramethaphosphate sodium complexes, show significant advantages in connection with doxycycline and known salts and complexes thereof, and human serum, one of the disadvantages of the tetracycline complex, which has long been known as an antibacterial agent. This is especially so when it comes to the incoherence of the natural bactericidal action of humanserum.

독씨싸이클린 테트라메타포스페이트 소듐복합체의 또 다른 몇가지 장점은 생물학적 유용성의 특출, 광역의 항세균스텍트럼, 소량의 투여량, 1일 1회투여, 24시간 또는 그 이상 혈액 및 조직수준유지, 위의 부작용완화, 뛰어난 위액의 안정 및 결정형태로 안정성이 장기 지속된다는 것 등이다.Some of the other benefits of the doxycycline tetramethaphosphate sodium complex include: bioavailability, widespread antibacterial spectrum, small doses, once daily, maintenance of blood and tissue levels for 24 hours or more, and alleviation of stomach side effects. In addition, the stability of the gastric fluid and the crystal form of the long-term stability.

염류와 인산이 부가된 다양한 테트라 싸이클린 복합체는 문헌에 기술되어 있다.Various tetracycline complexes with added salts and phosphoric acid are described in the literature.

미국 특허번호 2791609는 낮은 용해성과 고혈압을 유발하는 복합체인 테트라싸이클린 헥사메타포스페이트에 관하여 기술하고 있다.US Pat. No. 2791609 describes tetracycline hexametaphosphate, a complex that causes low solubility and hypertension.

그러나 이와 유사한, 예컨데 독씨싸이클린 헥사메타포스페이트는 물에 난용성이고 저혈압을 유발함으로서 임상적 유용성이 결여되고 있다.Similar, for example, doxycycline hexametaphosphate is poorly soluble in water and lacks clinical utility by causing hypotension.

미국 특허번호 3053892는테트라싸이클린 1몰당 HPO3, 1-4몰 비율로 메타포스포릭에시드와 테트라싸이클린의 복합체 제조방법을 기술하고 있다.US Patent No. 3053892 describes a method for preparing a complex of metaphosphoric acid and tetracycline at a ratio of 1-4 moles of HPO 3 per mole of tetracycline.

미국 특허번호 3068264는 포스포릭에시드와 알루미늄 및 테트라싸이클린의 복합체에 대하여 기술하고 있다. 이러한 복합체들은 pH6.5-pH8.0에서는 용해되나 pH3-pH5에서는 실제적으로 용해되지 않는다.US Patent No. 3068264 describes complexes of phosphoric acid with aluminum and tetracycline. These complexes dissolve at pH6.5-pH8.0 but practically do not dissolve at pH3-pH5.

테트라싸이클린, 알류미늄 메타포스페이트 사이의 몰비율은 1 : 4 : 12 또는 1 : 4 : 8이다.The molar ratio between tetracycline and aluminum metaphosphate is 1: 4: 12 or 1: 4: 8.

위에서 말한 복합체들은 알루미늄이 테트라싸이클린의 항균작용과 비보(ViVo)에서 간섭함으로서 임상적 적용을 하지 않고 있다.The complexes mentioned above have not been clinically applied because aluminum interferes with tetracycline's antimicrobial activity and ViVo.

포루투갈 특허번호 54708과 그의 부수특허는 무수상태에서 무엇보다도 α-6-데옥씨-5-하이드록씨 테트라싸이클린의 폴리메타포스페이트 복합체의 제조방법과 아울러 새로운 헥사메타포스페이트 복합체의 제조방법을 설명하고 있다.Portuguese Patent No. 54708 and an ancillary patent describe a method for preparing a polymethaphosphate complex of α-6-deoxy-5-hydroxy tetracycline as well as a method for preparing a new hexametaphosphate complex in anhydrous state.

미국 특허번호 2791609의 기술은 수용성 매질로 반응시키고 있는 반면 기타의 다른 특허는 상기 복합체를 무수매질을 사용하여 실시한 제조방법을 기술하고 있다.While the technique of US Pat. No. 2791609 is reacted with a water soluble medium, other patents describe a process in which the complex is carried out using anhydrous medium.

본 발명은 알칼리금속의 폴리메타포스페이트 제조와 α-6-데옥씨-5-하이드록씨 테트라싸이클린의 폴리메타포스페이트의 제조에 관한 것을 기술하고 있으며 여기에서 메타포스포릭에시드(HPO3)n의 중합도는 복합체내에서 균일하며 (HPO3)n은 4량체로 즉 n=4이다. 포루투갈 특허번호 54708과 그의 관계되는 특허에 관한 제조공정에 따라 알칼리 금속의 폴리메타포스페이트 복합체와 독씨싸이클린은 엄격한 무수상태의 매질을 사용하여 제조된다.The present invention describes the preparation of polymethaphosphate of alkali metals and the preparation of polymethaphosphate of α-6-decoxy-5-hydroxy tetracycline, wherein the degree of polymerization of metaphosphoric acid (HPO 3 ) n is It is homogeneous in the complex and (HPO 3 ) n is tetramer, ie n = 4. Polymethaphosphate composites and doxycycline of alkali metals are prepared using a strict anhydrous medium in accordance with the manufacturing process for Portuguese Patent No. 54708 and its related patents.

본 발명은 공정은 헥사메타포스페이트의 복합체 대신에 트리메타포스페이트 복합체를 수득하고 무수매질 대신 다량의 물을 엄격히 조절하는 조건하에서 반응을 진행시키는 것임으로 포루투갈 특허번호 54708에 기술된 것과는 전혀 상이한 것이다.The present invention is completely different from that described in Portuguese Patent No. 54708 in that the process is to obtain a trimethaphosphate complex instead of a complex of hexametaphosphate and to proceed the reaction under conditions that strictly control a large amount of water instead of anhydrous medium.

이소푸로판올의 첨가로 단리가 진행될때 새로운 복합체는 분자식(C22H24N2O3)3·(HPO8)3·NaPO3·

Figure kpo00001
·6H2O인 솔베이트 형태로 침전된다.When the isolation proceeds with the addition of isopropanol, the new complex is formed by the molecular formula (C 22 H 24 N 2 O 3 ) 3 · (HPO 8 ) 3 · NaPO 3 ·
Figure kpo00001
Precipitates in the form of a solution of 6H 2 O.

위에서 언급한 침전물을 이소푸로판올 대신에 순수한 에탄올만으로 단리를 하면 에탄올레이트/하이드레이트 형태하에서 새로운 복합체가 결정화 된다.Isolation of the above-mentioned precipitate with pure ethanol instead of isofuropanol results in crystallization of the new complex under ethanolate / hydrate form.

반응혼합시 물의 량은 독씨싸이클린의 1몰당 최소 2몰이 반응되며 4몰 이상이 되어서는 안된다. 메타포스포릭에시드는 공지의 방법으로 제조하되 복합체 제조전에 하는 것이 바람직하다. 포스포러스 펜톡사이드와 클로로포름과 같은 불활성 용매에 화학양론적 량의 물을 사용하여 제조하는것이 바람직한 방법이다.The amount of water in the reaction mixture should be at least 2 moles per 1 mole of doxycycline and should not be more than 4 moles. Metaphosphoric acid may be prepared by a known method, but before the composite is prepared. It is a preferred method to use stoichiometric amounts of water in an inert solvent such as phosphorus pentoxide and chloroform.

메타포스포릭에시드가 형성된 후에 반응 혼합물의 량과 같은 에탄올로 희석한 후 물을 첨가한 후 모노하이드레이트 독씨싸이클린을 가한다.After the metaphosphoric acid is formed, it is diluted with the same amount of ethanol as the amount of the reaction mixture, and then water is added, followed by addition of monohydrate doxycycline.

4몰의 메타포스포릭에시드당 3몰의 독씨싸이클린 모노하이드레이트를 첨가한다.3 moles of doxycycline monohydrate are added per 4 moles of metaphosphoric acid.

메타포스포릭에시드 용액에 독씨싸이클린을 첨가하는 속도는 용액안의 반응 혼합물을 유지하는 방법과 같이 조절하여야 한다. 연속적으로 나누어진 량으로 메탄올을 첨가하는 것은 결과적으로 독씨싸이클린의 분해를 완결하는데 도움을 줄 것이다.The rate of addition of doxycycline to the metaphosphoric acid solution should be controlled as in the method of maintaining the reaction mixture in the solution. Adding methanol in successive aliquots will eventually help complete the decomposition of doxycycline.

다음에 소듐하이드록싸이드의 메탄올 용액을 4몰의 메타포스포릭에시드당 1몰의 비율로 첨가한다. 반응화합물에 이소푸로판올의 첨가는 이소푸로판올과 물의 솔베이트와 같이 테트라메타포스페이트 소듐 복합체의 결정화를 가져온다.A methanol solution of sodium hydroxide is then added at a rate of 1 mole per 4 moles of metaphosphoric acid. The addition of isopropanol to the reaction compound results in crystallization of the tetramethaphosphate sodium complex, as isosorbate of isopropanol and water.

내복투약시 테트라메타포스페이트 소듐 복합체는 매우 신속히 흡수되며, 24시가 경과후에도 혈청농도는 최저 치료 효과농도 이상을 유지한다.Tetramethaphosphate sodium complexes are absorbed very rapidly during oral administration, and serum concentrations are maintained above the lowest therapeutic effect level after 24 hours.

다음 표는 두 그룹으로 나누어진 12명의 건강한 지원자들에게 각기 독씨싸이클린 베이스로 100mg과 200mg을 내복 투약한후 순준을 집계한 것이다.The following table summarizes the level of compliance after dosing 100 mg and 200 mg of doxycycline base to 12 healthy volunteers divided into two groups.

첫번째 그룹에서는 독씨싸이클린 테트라포스페이트소듐복합체와 부형제인 유당을 포함하는 1캡슐을 투약하고 두번째 그룹에서는 상기의 복합체를 2캡슐 투여했다. 혈액의 샘플은 투약후 0.1/2, 1, 2, 3, 4, 5, 6, 12, 24시간 후에 수집되었다. 혈청의 농도는 미생물학적으로 조사하였다.In the first group, one capsule containing the doxycycline tetraphosphate sodium complex and the excipient lactose was administered, and in the second group, two capsules of the complex were administered. Samples of blood were collected 0.1 / 2, 1, 2, 3, 4, 5, 6, 12, 24 hours after dosing. Serum concentrations were examined microbiologically.

Figure kpo00002
Figure kpo00002

이러한 수치는 독씨싸이클린이나 독씨싸이클린 복합체에 관하여 문헌에 발표된 것보다 훨씬 높은 것이며, 또한 탁월한 생화학적 유용성을 나타내고 있다.These figures are much higher than those published in the literature on doxycycline or doxycycline complexes, and also show excellent biochemical utility.

그러나 독씨싸이클린과 선행기술인 독씨싸이클린 유도체와 비교시 본 발명에 따른 독씨싸이클린 테트라메타포스페이트 소듐 복합체의 주된 장점은 인간혈청의 자연적 항균작용에 대한 간섭도가 현저히 경감된다는 것이다. 테트라싸이클린 특히 독씨싸이클린이 비보(ViVo), 비트로(Vitro)에서 혈청의 항균작용에 간여한다는 것은 이미 잘 알려진 사실이다(Forsgren, A. and Gnarpe, H.;Anrimicrobial Agents and Chemotherapy, 3,711-715(1973) ; Forsgren, A. and Gnarpe, H.: Nature New Biology, 244, 82-83(1973)).However, the main advantage of the doxycycline tetramethaphosphate sodium complex according to the present invention compared to doxycycline and the prior art doxycycline derivative is that the interference with respect to the natural antibacterial action of human serum is significantly reduced. It is well known that tetracycline, especially doxycycline, is involved in the antimicrobial activity of serum in ViVo and Vitro (Forsgren, A. and Gnarpe, H .; Anrimicrobial Agents and Chemotherapy, 3,711-715 (1973)). Forsgren, A. and Gnarpe, H .: Nature New Biology, 244, 82-83 (1973).

본 발명의 목적인 새로운 복합체의 인간혈청 살균작용에 대한 효과를 독씨싸이클린 하이드로 클로라이드의 효과와 비교하였다.The effect on the human serum bactericidal activity of the new complex, which is the object of the present invention, was compared with that of doxycycline hydrochloride.

인간혈청내 일정기간 생존하는 박테리아수를 독씨싸이클린 하이드로 클로라이드의 조제물과 같은 량의 독씨싸이클린 베이스의 복합체를 포함하는 동등한 조제물로 같은 시간에 조사하였다.The number of bacteria surviving in human serum for a period of time was investigated at the same time with an equivalent formulation comprising the same amount of doxycycline-based complex as the preparation of doxycycline hydrochloride.

인간 혈청내 생존박테리아(E, Coli)의 수는 항균제의 첨가없이 0-2시간동안 배양후 독씨싸이클린 하이드로클로라이드(10㎍/ml)와 조사하고 또한 독씨싸이클린 테트라메타포스페이트 소듐 복합체(10㎍/ml)가 포함된 상테에서 조사하였다.The number of viable bacteria (E, Coli) in human serum was investigated with doxycycline hydrochloride (10 μg / ml) after incubation for 0-2 hours without the addition of antimicrobial agents and also with doxycycline tetramethaphosphate sodium complex (10 μg / ml). ) Were investigated.

2시간 배양후 항균제의 첨가가 없는 상태에서 생존하는 박테리아의 수는 2×106에서 5.5×103으로 감소되어지는 반면, 독씨싸이클린을 사용한 실험에서는 잔존 박테리아수는 5×105-이었고 독씨싸이클린 테트라메타포스페이트 복합체를 사용했을 때에는 2.5×103이었다.After 2 hours of incubation, the number of bacteria that survived without the addition of antimicrobial agents was reduced from 2 × 10 6 to 5.5 × 10 3 , while the number of remaining bacteria in the experiments with doxycycline was 5 × 10 5- and doxycycline When tetramethaphosphate complex was used, it was 2.5 * 10 <3> .

같은 두시간 동안에 독씨싸이클린 테트라메타포스페이트 소듐 화합물이 간섭하지 않는 반면에, 독씨싸이클린 분자가 혈청내에서 항균작용간섭이 매우 강하다는 것은 근본적으로 중요한 사실이다.While the doxycycline tetramethaphosphate sodium compound does not interfere in the same two hours, it is fundamentally important that the doxycycline molecule is highly resistant to antimicrobial activity in serum.

즉, 혈청의 항균작용이 완전하게 작용할 수 있다는 사실로 치료기간을 단축하고, 또 그것에 의하여 비보(ViVo)내에서 저하아성 계통을 형성하는 가능성을 최소로 제한할 수 있게 된다.In other words, the fact that the antimicrobial action of the serum can be fully functioned, the treatment period can be shortened, thereby minimizing the possibility of forming a hypoglycemic lineage in ViVo.

이소푸로판올/물의 솔베이트와 에탄올/물의 솔베이트는 동일한 미생물학적 및 약학적 활동을 기하고 그리고 실온에서 안정성을 유지한다.Isopropanol / water sorbate and ethanol / water sorbate exhibit the same microbiological and pharmaceutical activity and remain stable at room temperature.

[실시예]EXAMPLE

(1) 포스포러스 펜톡사이드로부터 새로이 조제된 4.33g의 메타포속포릭에시드에 100ml의 클로로포름을 가한후 잘저으면서 100ml의 메탄올을 가했다. 약 15분간 저어준 다음 1ml의 물과 20g의 α-6-데옥씨-5-하이드록시 테트라싸이클린 모노하이드테이트(961mcg/mg)을 용액을 투명하게 보존하기 위하여 첨가했다.(1) 100 ml of chloroform was added to 4.33 g of a metaphosphoric acid, which was newly prepared from phosphorus pentoxide, and then 100 ml of methanol was added with stirring. After stirring for about 15 minutes, 1 ml of water and 20 g of α-6-deoxyc-5-hydroxy tetracycline monohydrate (961mcg / mg) were added to keep the solution transparent.

용액을 여과시킨 다음 0.574g의 소듐하이드록싸이드를 17.5ml의 메탄올에 용해했다. 15분간 저어준 후 430ml의 이소푸로판올을 가했다. 이러한 방식으로 결정화 되어가는 생성물을 여과한 후 이소푸로판올로 세척하고 35-40℃에서 건조했다.The solution was filtered and 0.574 g sodium hydroxide was dissolved in 17.5 ml methanol. After stirring for 15 minutes, 430 ml of isopropanol was added. The product, which crystallized in this way, was filtered off, washed with isopropanol and dried at 35-40 ° C.

다음과 같은 특성을 지닌 분자식(C22H24N2O8)3·(HPO3)3·NaPO3·

Figure kpo00003
·6H2O인 생성물 21g을 얻었다.Molecular formula (C 22 H 24 N 2 O 8 ) 3 · (HPO 3 ) 3 · NaPO 3 ·
Figure kpo00003
21 g of product, 6H 2 O, were obtained.

자외선 흡수 : 349nm에서

Figure kpo00004
238,266nm에서
Figure kpo00005
307(1% HCl-메탄올 용액)UV absorption: at 349nm
Figure kpo00004
At 238,266nm
Figure kpo00005
307 (1% HCl-Methanol Solution)

고유광회전도 : /α/D32°-86°(C=0.5, 1%HCl-메탄올 용액)Natural light rotation: /α/D32°-86°(C=0.5, 1% HCl-methanol solution)

1% 수용액의 pH : 2.8, 독씨싸이클린정량분석 : 70.21%PH of 1% aqueous solution: 2.8, Doxycycline quantitative analysis: 70.21%

물에 대한 용해도 : 335mg/mlSolubility in water: 335 mg / ml

(2)이소푸로판올을 순수한 에탄올로 바꾸어 (1)항을 반복했다.(2) The isopropanol was changed to pure ethanol and the item (1) was repeated.

그 결과 분자식 (C22H24N2O8)3·(HPO3)3·NaPO3·

Figure kpo00006
·6H2O인 물과 에탄올의 솔베이트와 같은 새로운 복합체가 침전되었다.As a result, the molecular formula (C 22 H 24 N 2 O 8) 3 · (HPO 3) 3 · NaPO 3 ·
Figure kpo00006
A new complex was precipitated, such as a sorbate of 6H 2 O water and ethanol.

Claims (4)

(정정)실온에서 메타포스포릭에시드와 α-6-데옥시-5-하이드록시 테트라싸이클린 모노하이드레이트를 HPO3와 α-6-데옥시-5-하이드록시 테트라싸이클린 모노하이드레이트의 몰비를 4 : 3으로 하여 클로로포름, 메탄올 및 물로 구성된 매질내에서 반응시켜 얻어진 테트라포스페이트 복합체중 하나의 HPO3를 NaOH-메탄올 수용액으로 중화시키고 이소푸로판올을 가하여 복합체를 결정화시키는 것을 특징으로 하는 구조식이 (C22H24N2O8)3·(HPO3)3·NaPO3·
Figure kpo00007
·6H2O인 솔베이트로 표현되는 α-6-데옥시-5-하이드록시 테트라싸이클린과 소듐테트라메타포스페이트의 수용성 복합체를 제조하는 방법(여기에서 메타포스포릭에시드의 중합체는 복합체내에서 n=4로 균일하다).(Correction) The molar ratio of metaphosphoric acid and α-6-deoxy-5-hydroxy tetracycline monohydrate at room temperature with HPO 3 and α-6-deoxy-5-hydroxy tetracycline monohydrate as 4: 3. A structural formula characterized by neutralizing HPO 3 in one of the tetraphosphate complexes obtained by reaction in a medium consisting of chloroform, methanol and water with an aqueous NaOH-methanol solution and adding isopropanol to crystallize the complex (C 22 H 24 N 2). O 8) 3 · (HPO 3 ) 3 · NaPO 3 ·
Figure kpo00007
A method for preparing a water-soluble complex of α-6-deoxy-5-hydroxy tetracycline and sodium tetramethaphosphate represented by 6H 2 O, wherein the polymer of metaphosphoric acid is n = 4 in the complex Uniform). (정정) 제1항에 있어서, 폴리메타포스포릭에시드는 포스포러스펜톡싸이드와 클로로포름에 화학양론적 비율로 물이 혼합된 용액으로부터 제조됨을 특징으로 하는 방법.(Correction) The method according to claim 1, wherein the polymetaphosphoric acid is prepared from a solution in which water is mixed in a stoichiometric ratio with phosphorus pentoxide and chloroform. (정정) 제1항에 있어서, 폴리메타포스포릭에시드를 α-6-데옥시-5-하이드록시 테트라싸이클린 모노하이드레이트 1몰당 2 내지 4몰의 물을 포함하는 메탄올에 희석하여 반응시킴을 특징으로 하는 방법.(Correction) The method according to claim 1, wherein the polymethaphosphoric acid is reacted by diluting with methanol containing 2 to 4 moles of water per mole of α-6-deoxy-5-hydroxy tetracycline monohydrate. Way. (정정) 실온에서 메타포스포릭에시드와 α-6-데옥시-5-하이드록시테트라싸이클린 모노하이드레이트를 HPO3와 α-6-데옥시-5-하이드록시 테트라싸이클린 모노하이드레이트의 몰비를 4 : 3으로 하여 클로로포름, 메탄올 및 물로 구성된 매질내에서 반응시켜 얻어진 테트라메타포스페이트 복합체중 하나의 HPO3를 NaOH-메탄올 수용액으로 중화시키고 무수에탄올로 복합체를 결정화시키는 것을 특징으로 하는 구조식이 (C22H24N2O8)3·(HPO3)3·NaPO3·
Figure kpo00008
·6H2O인 에탄올과 물의 솔베이트로 표현되는 α-6-데옥시-5-하이드록시 테트라싸이클린과 소듐테트라메타포스페이트의 수용성 복합체를 제조하는 방법.(Correction) At room temperature, metaphosphoric acid and α-6-deoxy-5-hydroxytetracycline monohydrate were used in the molar ratio of HPO 3 and α-6-deoxy-5-hydroxy tetracycline monohydrate as 4: 3. Structural formula (C 22 H 24 N 2 O) characterized by neutralizing HPO 3 of one of the tetramethaphosphate complexes obtained by reaction in a medium consisting of chloroform, methanol and water with an aqueous NaOH-methanol solution and crystallizing the complex with anhydrous ethanol. 8) 3 · (HPO 3) 3 · NaPO 3 ·
Figure kpo00008
A method for producing a water-soluble complex of α-6-deoxy-5-hydroxy tetracycline and sodium tetramethaphosphate represented by sorbent of 6H 2 O and sorbate of water.
KR1019810004468A 1980-11-25 1981-11-19 Process for the preparation of alpha-6-deoxy-5-hydroxy tetra cycline and sodium tetrametaphosphate complexes KR860000450B1 (en)

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