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Stabilization of quinapril by incorporating hydrogen bonding interactions.

Roy BN, Singh GP, Godbole HM, Nehate SP - Indian J Pharm Sci (2009)

Bottom Line: In the present study stability of various known solvates of quinapril hydrochloride has been compared with nitromethane solvate.Nitromethane solvate was found to be more stable compared to other known solvates.Quinapril tris(hydroxymethyl)amino methane salt found to be stable even at 80 degrees for 72 h i.e. hardly any formation of diketopiperazine and diacid impurity.

View Article: PubMed Central - PubMed

Affiliation: Lupin Ltd. (Research Park), 46A, 47A - Nande Village, Mulshi Taluka, Pune-411 042, India.

ABSTRACT
In the present study stability of various known solvates of quinapril hydrochloride has been compared with nitromethane solvate. Nitromethane solvate was found to be more stable compared to other known solvates. Single crystal X-ray diffraction analysis of quinapril nitromethane solvate shows intermolecular hydrogen bonding between quinapril molecule and nitromethane. Stabilization of quinapril by forming strong hydrogen bonding network as in case of co-crystals was further studied by forming co-crystal with tris(hydroxymethyl)amino methane. Quinapril free base forms a stable salt with tris(hydroxymethyl)amino methane not reported earlier. Quinapril tris(hydroxymethyl)amino methane salt found to be stable even at 80 degrees for 72 h i.e. hardly any formation of diketopiperazine and diacid impurity. As expected single crystal X-ray diffraction analysis reveals tris(hydroxymethyl)amino methane salt of quinapril shows complex hydrogen bonding network between the two entities along with ionic bond. The properties of this stable salt - stable in solid as well as solution phase, might lead to an alternate highly stable formulation.

No MeSH data available.


Single Crystal X-ray Diffraction study of quinapril hydrochloride nitromethane solvate.(a). Packing diagram with hydrogen bonding interaction viewed down a-axis depicting the H-bonded layered network for the compound. (b) Close-up view depicting the hydrogen bonding interaction of chloride anion and lattice nitromethane molecule in the 21 screw related cleft (dotted blue line) by the quinapril monoanion by dimeric association. (c) ORTEP diagram with atom numbering scheme of the Quinapril hydrochloride along with lattice nitromethane molecule (30% probability factor for the thermal ellipsoids and only one position of the isotropic ethyl group of the ethyl acetate moiety is shown in the figure for clarity.)
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Figure 0004: Single Crystal X-ray Diffraction study of quinapril hydrochloride nitromethane solvate.(a). Packing diagram with hydrogen bonding interaction viewed down a-axis depicting the H-bonded layered network for the compound. (b) Close-up view depicting the hydrogen bonding interaction of chloride anion and lattice nitromethane molecule in the 21 screw related cleft (dotted blue line) by the quinapril monoanion by dimeric association. (c) ORTEP diagram with atom numbering scheme of the Quinapril hydrochloride along with lattice nitromethane molecule (30% probability factor for the thermal ellipsoids and only one position of the isotropic ethyl group of the ethyl acetate moiety is shown in the figure for clarity.)

Mentions: ORTEP diagram of the quinapril nitromethane solvate is depicted in fig. 4c. Details of crystallographic data are summarized in Table 4. In an attempt to understand the interactions of the chloride and lattice nitromethane molecule with the quinapril monoanion, we have analyzed the packing and hydrogen bonding interaction of the compound in detail. Packing diagram of the compound with various hydrogen bonding interactions viewed down the a-axis for the compound is shown in fig 4a. Pairs of the protonated quinapril molecules are oriented with the flexible tethered phenyl terminal in opposite direction along c-axis to make effective intermolecular N-H…O interaction from either end between the protonated amine and the carboxylic acid oxygen O1 [N(2)…O(1)= 2.820(7) Å, < N(2)-H(2A)…O(1)= 164°] generating a cleft down a-axis. These dimeric protonated quinapril molecules are set along b-axis generating a layered network with 21 screw related cavities arranged alternately. It is interesting to note that the chloride anion and the lattice nitromethane molecules via various hydrogen bonding interactions occupy these cavities. Close-up view depicting the encapsulation of the chloride ion and nitromethane molecule is shown in fig. 4c. Chloride anion is anchored inside the cavity by involvement of three hydrogen bonding interactions O-H…Cl between the carboxylic hydrogen H2, N-H…Cl with the protonated amine and C-H…Cl of the methylene hydrogen H2B of the six membered rings. The methyl hydrogen of the nitromethane present inside the cavity are involved in strong intermolecular C-H…O interaction (C(26)….O(3)= 3.514(8) Å < C(26)-H(26B)….O(3)= 171°) with the ketonic oxygen O3. In addition to the above interactions, weak intramolecular C-H…O contact exist between (i) ketonic oxygen O3 and the H12 attached to the asymmetric carbon and (ii) the acetate oxygen O4 with the H11 of the heterocyclic ring. Details of all these pertinent hydrogen-bonding interactions, along with symmetry code, are given in Table 6.


Stabilization of quinapril by incorporating hydrogen bonding interactions.

Roy BN, Singh GP, Godbole HM, Nehate SP - Indian J Pharm Sci (2009)

Single Crystal X-ray Diffraction study of quinapril hydrochloride nitromethane solvate.(a). Packing diagram with hydrogen bonding interaction viewed down a-axis depicting the H-bonded layered network for the compound. (b) Close-up view depicting the hydrogen bonding interaction of chloride anion and lattice nitromethane molecule in the 21 screw related cleft (dotted blue line) by the quinapril monoanion by dimeric association. (c) ORTEP diagram with atom numbering scheme of the Quinapril hydrochloride along with lattice nitromethane molecule (30% probability factor for the thermal ellipsoids and only one position of the isotropic ethyl group of the ethyl acetate moiety is shown in the figure for clarity.)
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2865811&req=5

Figure 0004: Single Crystal X-ray Diffraction study of quinapril hydrochloride nitromethane solvate.(a). Packing diagram with hydrogen bonding interaction viewed down a-axis depicting the H-bonded layered network for the compound. (b) Close-up view depicting the hydrogen bonding interaction of chloride anion and lattice nitromethane molecule in the 21 screw related cleft (dotted blue line) by the quinapril monoanion by dimeric association. (c) ORTEP diagram with atom numbering scheme of the Quinapril hydrochloride along with lattice nitromethane molecule (30% probability factor for the thermal ellipsoids and only one position of the isotropic ethyl group of the ethyl acetate moiety is shown in the figure for clarity.)
Mentions: ORTEP diagram of the quinapril nitromethane solvate is depicted in fig. 4c. Details of crystallographic data are summarized in Table 4. In an attempt to understand the interactions of the chloride and lattice nitromethane molecule with the quinapril monoanion, we have analyzed the packing and hydrogen bonding interaction of the compound in detail. Packing diagram of the compound with various hydrogen bonding interactions viewed down the a-axis for the compound is shown in fig 4a. Pairs of the protonated quinapril molecules are oriented with the flexible tethered phenyl terminal in opposite direction along c-axis to make effective intermolecular N-H…O interaction from either end between the protonated amine and the carboxylic acid oxygen O1 [N(2)…O(1)= 2.820(7) Å, < N(2)-H(2A)…O(1)= 164°] generating a cleft down a-axis. These dimeric protonated quinapril molecules are set along b-axis generating a layered network with 21 screw related cavities arranged alternately. It is interesting to note that the chloride anion and the lattice nitromethane molecules via various hydrogen bonding interactions occupy these cavities. Close-up view depicting the encapsulation of the chloride ion and nitromethane molecule is shown in fig. 4c. Chloride anion is anchored inside the cavity by involvement of three hydrogen bonding interactions O-H…Cl between the carboxylic hydrogen H2, N-H…Cl with the protonated amine and C-H…Cl of the methylene hydrogen H2B of the six membered rings. The methyl hydrogen of the nitromethane present inside the cavity are involved in strong intermolecular C-H…O interaction (C(26)….O(3)= 3.514(8) Å < C(26)-H(26B)….O(3)= 171°) with the ketonic oxygen O3. In addition to the above interactions, weak intramolecular C-H…O contact exist between (i) ketonic oxygen O3 and the H12 attached to the asymmetric carbon and (ii) the acetate oxygen O4 with the H11 of the heterocyclic ring. Details of all these pertinent hydrogen-bonding interactions, along with symmetry code, are given in Table 6.

Bottom Line: In the present study stability of various known solvates of quinapril hydrochloride has been compared with nitromethane solvate.Nitromethane solvate was found to be more stable compared to other known solvates.Quinapril tris(hydroxymethyl)amino methane salt found to be stable even at 80 degrees for 72 h i.e. hardly any formation of diketopiperazine and diacid impurity.

View Article: PubMed Central - PubMed

Affiliation: Lupin Ltd. (Research Park), 46A, 47A - Nande Village, Mulshi Taluka, Pune-411 042, India.

ABSTRACT
In the present study stability of various known solvates of quinapril hydrochloride has been compared with nitromethane solvate. Nitromethane solvate was found to be more stable compared to other known solvates. Single crystal X-ray diffraction analysis of quinapril nitromethane solvate shows intermolecular hydrogen bonding between quinapril molecule and nitromethane. Stabilization of quinapril by forming strong hydrogen bonding network as in case of co-crystals was further studied by forming co-crystal with tris(hydroxymethyl)amino methane. Quinapril free base forms a stable salt with tris(hydroxymethyl)amino methane not reported earlier. Quinapril tris(hydroxymethyl)amino methane salt found to be stable even at 80 degrees for 72 h i.e. hardly any formation of diketopiperazine and diacid impurity. As expected single crystal X-ray diffraction analysis reveals tris(hydroxymethyl)amino methane salt of quinapril shows complex hydrogen bonding network between the two entities along with ionic bond. The properties of this stable salt - stable in solid as well as solution phase, might lead to an alternate highly stable formulation.

No MeSH data available.