Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-12
2001-09-11
Oswecki, Jane C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S561000, C548S562000
Reexamination Certificate
active
06288241
ABSTRACT:
The present invention relates to a new crystalline form of 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid guaiacyl ester, a process for its preparation and to pharmaceutical compositions endowed with antiinflammatory, analgesic and antipyretic activity containing same.
The ester of 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid (hereinafter referred to as MED 15, form 1) is a known compound.
In fact, U.S. Pat. No. 4,882,349 discloses a class of N-mono-substituted and N,N-disubstituted amides of 1-methyl-5-p-toluoylpyrrole-2-acetic acid (known as Tolmetin) endowed of anti-inflammatory, analgesic, antipyretic, antisecretive and antitussive properties.
U.S. Pat. No. 4,578,481 claims a specific compound, endowed with valuable pharmacological activity, encompassed in the above-mentioned class, precisely 1-methyl-5-p-toluoylpyrrole-2-acetamido-acetic acid guaiacyl ester (which is MED 15, form 1), and a process for its preparation.
The process disclosed in U.S. Pat. No. 4,578,481 presents some drawbacks, since it is not easily applicable on industrial scale and gives low yields.
According to the above-mentioned process, Tolmetin was reacted with N,N′-carbonyldiimidazole in tetrahydrofuran (THF), and aminoacetic acid ethyl ester hydrochloride was added to the reaction mixture.
Following a complex series of washings in order to remove the unreacted starting compounds, and crystallisation from benzene/cyclohexane, 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid ethyl ester was obtained. This compound was subsequently transformed into the corresponding acid.
The acid was reacted with N,N′-carbonyldiimidazole obtaining the corresponding imidazolide, to which a solution of guaiacol in THF was added.
From the reaction mixture, following several washings, neutralisation and crystallisation from benzene/cyclohexane MED 15 form 1 was obtained.
The main physico-chemical characteristics of MED 15 form 1 are shown in table 1, left column.
There are various known possibilities for the administration of any drug, thus this may be conveniently done per oral route, using suitable pharmaceutical formulations such as tablets, sugar-coated pills and capsules, or per rectal route using, for example, suppositories.
These administrations way present obvious advantages in comparison with the parenteral route (injectable route) because they do not need the presence of a physician or a person able to use a syringe.
Good manufacturing practices of the above-mentioned pharmaceutical formulations, suitable for an oral administration, request that several parameters, depending on the nature of the drug, be respected.
Non-limiting examples of such parameters are: stability of the drug utilised as starting materials in different environment conditions; stability during the production process; and stability of the final pharmaceutical formulations.
The drug utilised for the preparation of the above mentioned pharmaceutical formulations must be as pure as possible, and its stability during prolonged storage periods in different environment conditions must be controlled, avoiding the use of degraded drug, or drug having unexpectedly lower titre than the one requested by the production process. In such case the content of the drug present in a single sugar-coated pill or capsule would be undesirably lower than wanted.
The absorption of humidity decreases the drug titre because of the increase of the drug weight, which is due to its capacity to absorb water.
For this reason drugs which tend to absorb humidity must be protected during long term storage, for example using suitable dehydrating agents, or storing them in an environment protected from humidity.
Humidity may decrease drug titre also during the production process when the drug is exposed in normal conditions to humidity, without any protection.
The correct distribution of an exact amount, in weight, of drug in single sugar-coated pills or capsules is a critical factor, particularly when low drug dosages are utilised.
It is possible to reduce the dimension of drug particles to a suitable value, for example by milling, in order to obtain a correct distribution of a drug.
In fact, small particles are better distributed in constant amount, in single sugar-coated pills or capsules.
Since milling may provoke a certain degree of drug degradation, high stability to milling represents an important advantage for the preparation of capsules or sugar-coated pills containing the due amount of drug, avoiding the presence of degradation products.
Moreover, during milling, mechanical stress on the solid product may provoke polymorphic alteration, amorphization, and alteration of the crystalline shape or surface.
These alterations play a fundamental role in the subsequent technological process to which the product is undertaken and on the bio-pharmaceutical characteristics.
The stability of the active principle contained in the pharmaceutical composition is essential for determining the time of drug validity. In this period the drug can be administered without any risk, either due to the presence of an excessive quantity of potentially dangerous degradation products, or to low content of the active ingredient, lower than the established amount.
The stability of the drug in different storage conditions represents supplemental advantages both for patients and for the manufacturer; in fact, storage in controlled environment and frequent substitution of expired batches are avoided.
Any modification of the solid state of the orally administered drug, such as capsules, tablets or sugar-coated pills, which improves its physical and chemical stability, and gives rise to a significant advantage in comparison with less stable form of the same drug, would be a very desirable goal.
It is well known that a significant example of the above mentioned modifications includes a new crystalline form of the drug, which overcomes the above-mentioned drawbacks.
It is an object of the present invention to provide a new crystalline form of MED 15 (in the following as MED 15, form 2) which does not present the above-mentioned drawbacks.
A further scope of the present invention is to provide a process, which overcomes the drawbacks of the known methods. This process is industrially applicable with high yield and is suitable for preparing MED 15, form 2 with high degree of purity.
It has now been found that 1-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid guaiacyl ester of formula
presents the polymorphism phenomenon and in addition to the above-mentioned MED 15, form 1, it also exists in a second crystalline form, designated as MED 15, form 2, characterised by the following physico-chemical characteristics:
melting point: 133-136° C.;
DSC
Peak
136.2° C.
136.7° C.
Onset
132.5° C.
133.7° C.
Delta H
97.3 J/g
98.3 J/g
IR spectrum (presenting characteristic signals at the following wave numbers in cm
−1
)
3302.98
1550.27
1113.95
699.06
3092.37
1501.85
1037.43
620.38
2948.24
1480.85
1022.34
576.81 cm
−1
2842.00
1458.18
976.95
1785.85
1377.94
885.21
1762.26
1310.86
833.34
1646.73
1262.66
788.30
1626.80
1202.46
769.16
1607.82
1179.67
749.21
1564.93
1162.83
729.28
Some fundamental physico-chemical characteristic values (melting point, differential scanning calorimetry, DSC, and I.R. spectrum) are shown, for comparison purposes, in Table 1. These values show the difference between the two forms.
TABLE 1
Comparison between the physico-chemical characteristics (melting point, DSC, IR spectrum)
of MED 15, form 1, and form 2.
MED 15, form 1
MED 15, form 2
Melting point*
117-120° C.
132-136° C.
DSC**
Peak
129.5-130.9° C.
136.2- 136.7° C.
Onset
125.4-125.9° C.
132.5- 133.7° C.
Delta H
97.7-101.1 J/g
97.3-98.3 J/g
IR Spectrum***
3315.47
1486.29
968.53
636.42
3302.98
1550.27
1113.95
699.06
(wave numbers in cm
−1
)
3296.85
1455.29
936.82
621.99
3092.37
1501.85
1037.43
620.38
3066.96
1408.70
918.44
556.44
2948.24
1480.85
1022.34
576.81
2931.05
1375.95
882.01
2842.00
1458.18
976.95
2841.60
1312.38
838.68
1785.85
1377.94
885.21
1775.59
1261.40
786.11
1762.26
1310.86
833.34
Nixon & Vanderhye
Oswecki Jane C.
Sigma-Tau Farmaceutiche Riunite S.p.A.
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