This invention relates to new polymorphic form of sultamicillin tosylate and a process therefor.
FIELD OF THE INVENTION:
This invention specifically relates to a crystalline polymorphic form of sultamicillin
tosylate having advantages for use in antibacterial infections. The new form is more
stable and has enhanced bioavailability. The chemical name of sultamicillin tosylate is
1,1 -dioxopenicillanoyloxymethyl 6-(D-a-amino-a-phenylacetamido)penicillanate
tosylate (hereinafter "VD 1827 tosylate") represented by the following formula:
(Formula Removed)
The invention also discloses a process for the preparation of new polymorphic form of
sultamicillin tosylate.
BACKGROUND OF THE INVENTION:
Sultamicllin is a methylenedioxy linked conjugate of penicillanic acid 1,1- dioxide
(sulbactam) and ampicillin.
US 4,234,579 discloses sulbactam and esters thereof, which are readily hydrolysable in
vivo, for enhancing the effectiveness of beta-lactam antibiotics such as ampicillin.
US 4,244,951 discloses a novel conjugates of sulbactam and known penicillin antibiotics linked via methylenedioxy group.
US 4,432,987 discloses crystalline benzenesulfonate salts of sultamicillin. According to disclosure in column 1, lines 50 to 55, sultamicillin free base has poor handling characteristics and poor stability. Further, the patent teaches that the only salt of sultamicillin disclosed in the prior art is hydrochloride & due to poor solid state stability, it is susceptible to hydrolytic decomposition. It also poses problems particularly in aqueous formulations.
Crystalline forms are always preferable due to higher stability. Moreover, the crystalline form with enhanced bioavailability is more desirable.
US Patent No. 4,342,772 ('772) in general discloses ß-lactam compounds, antibacterial compositions thereof and method of use including sultamicillin for treatment of bacterial infections. The said patent designates 1, 1-dioxopenicillanoyloxymethyl 6-(D-α-amino-α -phenyl acetamido)penicillanate as VD 1827 tosylate, which possesses antibacterial property. Further, the advantages of VD 1827 are highlighted by giving comparative account of absorption levels of VD 1827 and existing hydrochloride salt. The patent also discloses method of its preparation and method of treating bacterial infections. Column 17 lines 25 -65 and column 18 lines up to 10 describe the preparation of sultamicillin tosylate. The products so obtained have melting point 141°-148°C & IR-spectrum of the products showed strong bands at: 1790, 1680, 1515 & 1325cm-1 . The compound has
been claimed to be strongly active against ß-lactamase producing bacteria, but it does not disclose the possible existence of different polymorphic forms.
To prepare pharmaceutical compositions containing VD 1827 tosylate for administration
to mammals in accordance with exacting health registration requirements of the US and
international health registration authorities, e.g. the FDA's Good Manufacturing Practices
("GMP"), there is a need to produce VD 1827 tosylate in as stable a crystalline form as
possible, especially a form having good physical and mechanical properties like high
melting range and better dissolution profile.
SUMMARY OF THE INVENTION:
One objective of the present invention is to produce a new polymorph of sultamycillin
tosylate designated herein after as Form 2.
Other objective is to produce new polymorph that has better dissolution profile and hence
better bioavailability so that it becomes available in the body as soon as it is taken as a
dose for faster action on the bacteria.
Yet other object is to provide a polymorph with better stability over the existing forms.
Another objective of the invention is to produce a new polymorph that should have
higher melting range that can withstand the heat generated during formulating the product
for finish doses.
Still another objective of the invention is to produce a new polymorph that has minimum
water content so that the extra weight taken to provide the effective amount of the drug
can be minimized.
BRIEF DESCRIPTION OF THE DRAWING:
Fig.l: Infra red spectrum of crystalline polymorphic form 2 of VD 1827 tosylate Fig.2: X-Ray Diffraction pattern of crystalline polymorphic form 2 of VD 1827 tosylate
Fig. 3: Differential scanning calorimetric curve of crystalline polymorphic form 2 of VD
1827tosylate
Fig 4: Differential scanning calorimetric curve of crystalline VD 1827 tosylate when
prepared by the method disclosed in '772.
Fig 5: X-Ray Diffraction pattern of crystalline polymorphic form 1 of VD 1827 tosylate
prepared by the method disclosed in' 772
We after prolonged research have found out that VD 1827 tosylate can exist in crystalline
polymorphic form, that is distinct from the one disclosed in the '772. Form 2 has
distinctly different physical properties such as melting point X ray diffraction and IR
spectrum. Further, the form 2 of this invention proves to have better stability due to its
higher melting point and bioavailability due to its higher dissolution rate as compared to
the one described and claimed in '772.
STATEMENT OF THE INVENTION:
Accordingly the present invention provides a novel polymorphic form 2 of Sultamicillin tosylate having the formula structure.
(Steucture Removed)
characterized by the following data :
a) Infrared absorption bands (cm-1): 2978,1793,1689,1498,1459,1326, 1175,1126,1009,975,684,570 (±5 cm-1)
b) Xray-powder diffraction peaks (26):
c) 5.52,6.46,11.02,12.10,12.88,13.22,14.30,14.78,15.24,15.92,16.46,18.20,18.62, 18.96,19.34,20.26,20.70,21.16,21.96,22.98,23.42,23.74,24.30,25.06,26.56,27.04, 27.36,28.04,28.76,29.30,29.80,31.28,32.04,34.64,34.90,36.40,38.80
d) Differential scanning calorimeter: Onset 174.73°C, Endset 179.76°C, Peak 177.52°C(±5°C).
In accordance with other aspect of this invention there is provided a process for the preparation of novel polymorphic form 2 of Sultamicillin tosylate having the characteristics as defined herein above comprising:
a) synthesizing Sultamicillin tosylate pure/recrystallised according to US patent no. 4,342,772
b) dissolving the compound obtained in step (a) in a polar organic solvent
c) crystallizing the polymorphic form 2 from the reaction mass followed by filtration and drying.
According to one of the embodiments of this invention, the polar organic solvents used in step (b) may be such as C1-C5 alkanols preferably methanol, ethanol, isopropanol, butanol.
According to other embodiment, the dissolving in step (b) may be carried out at a temperature in the range from 10° to 100°C preferably 30° to 80°C, more preferably from 50-60°C.
According to another embodiment, the crystallization temperature may vary from -5°C to +40°C preferably 0° to +30°C and more preferably from 0°C to 25°C.
Further, the sultamicillin base may be prepared by any traditional method using said
form 2.
Form 2 of this invention is characterized by the following infra red spectrum pattern:
2978,1793,1689, 1498,1459, 1326,1175,1126,1009, 975, 684, 570 (± 5 cm-1)
The invention is further characterized by the following XRD pattern expressed in terms
of "2 Theta" and "d" spacing (± 0.5)

(Table Removed)
The invention is still further characterized by the following XRD pattern expressed in terms of "2 Theta" and "d" spacing (± 0.5)

(Table Removed)
The invention is additionally characterized by the following DSC pattern: Onset 174.73°C, End set 179.76°C, Peak 177.52°C (± 5°C)
DETAILED DESCRIPTION OF THE INVENTION:
We have discovered that Form 2 of VD 1827 tosylate is distinctly different polymorph from the one VD 1827 tosylate (designated as form 1) as described in US Patent No. '772 The distinctness is very clear from the comparative data as given below pertaining to specific characteristics of the two polymorphs.
The major signals of polymorph 1, when prepared as per method disclosed in '772, are as given in table 1.
TABLE -1

(Table Removed)
Form 1 is further characterized by IR cm-1: 2993, 1676, 1521, 1326, 1174, 1121, 1011, 970,684, 570. and DSC pattern as follows (30-300°C, 10°C /min, N2; 50ml/min.):
On set 148.7°C, End set 172.3°C, Peak 168.2°C The melting point is 148°C Form 2 as claimed in the present invention has the following characteristics: XRD: (± 0.5)- Major Signals

(Table Removed)
IR (± 5 cm -1) :
2978,1793,1689, 1498,1459, 1326,1175, 1126, 1009, 975, 684, 570 DSC: (30-300°C, 10°C/min, N2; 50ml/min):
Onset 174.73°C, End set 179.76°C, Peak 177.52°C (± 5°C) Melting range: 160-175°C.
Dissolution profile: A) Dissolution in Water

(Table Removed)
B) Dissolution in 0.1 N HC1

(Table Removed)
We have discovered that the specific solvents and experimental conditions produce
a distinctly different crystalline polymorphic form 2 of VD 1827 tosylate.
The invention can further be described by taking following example, which may not
be considered limiting to the scope of the invention.
EXAMPLE 1:
Preparation of polymorphic form 2 of Sultamicillin tosylate
Sultamicillin tosylate (VD 1827 tosylate), 100 g, (available from preparation 30 of
US 4,342,772) was added to hot isopropyl alcohol, (1.0 ltr) and was stirred for lhr
at. Mass was cooled to 25°C followed by filtration and washing with isopropyl
alcohol. Cake was dried to give 86 g product. Melting range: 160-175°C.
IR (± 5 cm -1) :
2978, 1793,1689, 1498, 1459,1326,1175,1126, 1009, 975, 684, 570
XRD: (± 0.5) Major Signals and dissolution confirms the characteristics of Form 2 Example II
Preparation of polymorphic Form 2 of Sultamicillin tosvlate
100g of Sultamicillin tosylate (VD1827tosylate, prepared as per US patent 4,342,772) is taken in hot isopropyl alcohol (l.Oltr) at 50-60°C and the resultant reaction mixture is stirred at 50-60°C for dissolution of the material. Then the reaction mixture is cooled to 20-25°C and stirred at 20-25°C for l-2hr. The product, thus obtained, is filtered, followed by washing with isopropyl alcohol (100ml.) and dried to obtain polymorphic form 2 of Sultamicillin tosylate. Yield = 90g, (90%); Assay = 78.74%
Example III
Preparation of polymorphic Form 2 of Sultamicillin tosvlate
100g of crude Sultamicillin tosylate (crude VD1827tosylate, prepared as per US patent 4,342,772; assay = 72%) is taken in hot isopropyl alcohol (l.Oltr) at 50-60°C and the resultant reaction mixture is stirred at 50-60°C for dissolution of the material. Then the reaction mixture is cooled to 20-25°C and stirred. The product, thus obtained, is filtered, followed by washing with isopropyl alcohol (100ml.) and dried, to obtain polymorphic form 2 of Sultamicillin tosylate. Yield = 86g,(90%); assay = 77.34% Example IV
Preparation of Sultamicillin base from Sultamicillin tosvlate
100g of crude Sultamicillin tosylate Form 2 is dissolved in acetonitrile (200ml.) at 30-35°C and the resultant solution is cooled to 0-5°C. Then N,N diisopropyl ethyl amine (15ml) dissolved in isopropyl alcohol (100ml) is added dropwise to the
above cooled reaction solution at 0-5°C and the reaction mixture is further stirred for 10minutes. The reaction mixture is seeded with Sultamicillin base (3g) and the resultant reaction mixture is stirred at 0-5 °C for 30minutes. Then isopropyl alcohol (700ml) is added to it at 0-5 °C. in order to get complete crystallization of product. The product is filtered followed by washing with isopropyl alcohol (300ml.) and then finally with diisopropyl ether (300ml). The product is dried under vacuum. Yield = 72g,(~89%); assay = >99%
ADVANTAGES:
1) Product has better dissolution profile
2) It has higher melting range that gives better physical and mechanical properties contributing to better stability.
3) It has lesser water content, thus has more effective weight in the given weight as compared to the product having higher water content.

WE Claim:
1. Novel polymorphic form 2 of Sultamicillin tosylate and a process therefor having the
formula structure.
(Structure Removed)
characterized by the following data :
e) Infrared absorption bands (cm"1): 2978,1793,1689,1498,1459,1326, 1175,1126,1009,975,684,570 (±5 cm"1)
f) Xray-powder diffraction peaks (20): 5.52,6.46,11.02,12.10,12.88,13.22,14.30,14.78,15.24,15.92,16.46,18.20,18.62, 18.96,19.34,20.26,20.70,21.16,21.96,22.98,23.42,23.74,24.30,25.06,26.56,27.04, 27.36,28.04,28.76,29.30,29.80,31.28,32.04,34.64,34.90,36.40,38.80
g) Differential scanning calorimeter: Onset 174.73°C, Endset 179.76°C, Peak 177.52°C(±5°C).
2. A process for the preparation of novel polymorphic form 2 of Sultamicillin tosylate as
claimed in claim 1, which comprises:
(a) synthesizing Sultamicillin tosylate pure/recrystallised according to US patent no. 4,342,772,
(b) dissolving the compound obtained in step (a) in a polar organic solvent
(c) crystallizing Form 2 from the reaction mass followed by filtration and drying.
3. A process as claimed in claim 2 wherein the polar organic solvents are selected from
C1-C5 alkanols preferably methanol, ethanol, isopropanol, butanol.
4. A process as claimed in claim 2 wherein the dissolving in step (b) is carried out at a temperature in the range of 10° to 100°C preferably 30° to 80°C, more preferably from 50-60°C.
5. A process as claimed in claim 2 wherein the crystallization is effected at a temperature varying from -5°C to +40°C preferably 0° to +30°C and more preferably from 0°C to
25°C.
6. Novel polymorphic form 2 of Sultamicillin tosylate and a process therefore
substantially as herein described with reference to the examples and drawings.