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The Stability of Calcium Glucoheptonate Solutions

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The Stability of Calcium Glucoheptonate Solutions THE STABILITY OF CALCIUM GLUCOHEPTONATE SOLUTIONS BY RAJAGOPALAN SURYANARAYANAN M. Pharm., Banaras Hindu University, 1978 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN THE FACULTY OF GRADUATE STUDIES (Faculty of Pharmaceutical Sciences) Division of Pharmaceutics We accept this thesis as conforming to the required standard c RAJAGOPALAN SURYANARAYANAN, 1981 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date - ii - ABSTRACT Calcium glucoheptonate is official in the USP XX as Calcium Gluceptate and is described as the calcium salt of D-glycero-D-gulo- heptonic acid which is the a epimer of glucoheptonic acid. It is freely soluble in water. Since late 1976, solutions of calcium gluco• heptonate have shown a tendency to precipitate on storage. The problem of precipitation can be due to one or more of the following reasons: (i) change from an unstable to a stable modification (ii) presence of seed crystals (iii) differing proportions of a and 3 epimers in the calcium glucoheptonate obtained from various sources Calcium glucoheptonate was found to be amorphous while the precipi• tate was crystalline. Membrane filtration increased the time taken for precipitation to occur while autoclaving resulted in stable solutions. It can be postulated that the majority of seed crystals are excluded by filtration which results in increased stability and autoclaving destroys the seed crystals. When calcium glucoheptonate from different sources was used for the preparation of solutions, the time for precipitation varied with the commercial source (Table 1). The most stable solution was prepared from a salt described as calcium a-B glucoheptonate and the least stable was supplied as Calcium Gluceptate USP. - iii - Table 1. Stability of calcium glucoheptonate solution 26.7% w/v and proportion of a epimer in various commercial samples. Time for precipita• Proportion of a epimer Source tion (days) (percent) Pfanstiehl a-8' stable 51.8 Givaudan 8 71 .8 Italsintex 2 72.4 Pfanstiehl USP <1 100 It therefore seemed likely that, in addition to the presence of seed crystals, stability may depend on the relative proportions of the a and 3 epimers. It is interesting that to comply with the USP specifications, calcium glucoheptonate should be the unstable a epimer, although no procedure is given in the monograph for the identification or assay of the a form. Hence methods have been developed to identify and to deter• mine the proportions of the a and 6 epimers. An aqueous solution of calcium glucoheptonate was converted into a mixture of glucoheptonic acids and their corresponding y lactones by passage through a cation exchange column. The solution was freeze-dried and the acid-lactone mixture was completely converted to the y lactones using concentrated HCl. Trimethylsilyl (TMS) derivatives of the lactones were formed by reaction with trimethylsilylimidazole in pyridine. Gas chromatography on a 3% OV-225 column using a flame ionization detector gave two peaks. - iv - A control experiment using the TMS derivative of a reference sample of the y lactone of a-D-glucoheptonic acid gave a single peak having the same retention time as the second peak of the sample, thereby indicating that the second peak is due to the TMS derivative of this y lactone. The two GC peaks gave similar mass spectral patterns and subjecting the reference material to the same GC-MS analysis, confirmed that the peak 2 was the TMS derivative of the y lactone of a-p-glucoheptontecacid. Since the GC peaks 1 and 2 have different retention times but the same molecular ion and similar fragmentation patterns, the chemical structures of the two compounds must be very similar and hence peak 1 is attributed to the TMS derivative of the y lactone of 3-D-glticohe.ptontc acid. The relative proportions of the a and 6 epimers were calculated using the TMS deriva• tive of sucrose as an internal standard. The correlation between the stability results and the proportions of the a and 6 epimers in various commercial samples of calcium glucoheptonate is shown in Table 1. Hence it seems that all the three reasons postulated earlier have some role to play in the recrystallization of calcium glucoheptonate. By the use of elemental analysis, IR spectroscopy, DSC and GC-MS studies, the precipitate obtained from solutions of calcium glucoheptonate has been identified as a hydrate of calcium glucoheptonate. Attempts were made to develop stable oral and parenteral solutions containing glucoheptonate. All the oral formulations commenced precipita• tion within six months. Stable parenteral formulations can be prepared by autoclaving the final solution. If sterilization by filtration is desired, then the solution can be stabilized with calcium D-saccharate or calcium gluconate. - V - TABLE OF CONTENTS Pa^e ABSTRACT i i LIST OF TABLES x LIST OF FIGURES xi LIST OF SCHEMES xii LIST OF ABBREVIATIONS xiii ACKNOWLEDGEMENTS xiv PART A - THE STABILITY OF CALCIUM GLUCOHEPTONATE SOLUTIONS 1. INTRODUCTION 1 1.1 METHODS OF ANALYSIS OF CALCIUM GLUCOHEPTONATE 3 1.2 CHROMATOGRAPHY OF HEPTOSES AND HEPTONOLACTONES ' 3 1.2.1 Gas chromatography 3 A. Methyl derivative 4 B. Trimethylsilyl derivative 8 1.2.2 Paper chromatography 9 1.3 LACTONIZATION OF ALDONIC ACID 9 1.4 MASS SPECTROMETRY OF HEPTONOLACTONES 11 1.5 PHASE TRANSITIONS 11 1.5.1 Amorphous-crystalline transitions . 12 1.5.2 Hydrate anhydrous form transitions 13 1.5.3 Polymorphic transitions 14 - vi - Page 2. EXPERIMENTAL 15 2.1 APPARATUS 15 2.2 MATERIALS 16 2.3 STABILITY STUDIES OF CALCIUM GLUCOHEPTONATE SOLUTIONS 18 2.3.1 Solutions made from calcium glucoheptonate after heating at 120°C 18 2.3.2 Heat treatment of calcium glucoheptonate solutions 19 2.3.3 Membrane filtration of calcium glucoheptonate solutions 19 2.4 CHARACTERIZATION OF CALCIUM GLUCOHEPTONATE AND THE PRECIPITATE OBTAINED FROM SOLUTIONS OF CALCIUM GLUCOHEPTONATE 19 2.4.1 Elemental analysis 19 2.4.2 Thermal analysis 20 2.4.3 Infrared spectra 20 A. Preparation of solid samples 20 B. Preparation of solutions 20 2.4.4 Heat of solution 21 2.4.5 X-ray diffraction * 21 2.4.6 Equilibrium solubility 21 2.5 DEVELOPMENT OF A GAS CHROMATOGRAPHIC METHOD FOR ESTIMATING THE PROPORTIONS OF a AND 3 EPIMERS IN CALCIUM GLUCO• HEPTONATE 21 2.5.1 Selection of a substance for preliminary studies 21 2.5.2 Preparation of methyl derivative 22 A. Preparation of sodium methylsulfinylmethide 22 B. Derivative formation 22 - vii - Page 2.5.3 Preparation of trimethylsilyl derivative 23 A. N-trimethylsilylimidazole 23 B. Mixture of trimethylsilylimidazole, N,0-bis(trimethylsilyl) acetamide, and trimethylchlorosilane 23 C. Trimethylsilylimidazole in pyridine 24 2.5.4 Preparation of the trimethylsilyl derivative of calcium glucoheptonate 24 2.5.5 Lactone formation 27 2.5.6 Gas chromatography-mass spectrometry .30 2.5.7 Selection of internal standard 32 2.5.8 Optimization of GC conditions 32 A. Selection of stationary phase 33 B. Temperature programming 33 C. Injection temperature 34 D. Detector temperature 34 E. Optimization of reaction time 34 2.6 PREPARATION OF STANDARD CURVE OF THE y-LACTONE OF a-D-GLUCOHEPTONIC ACID 36 2.7 DETERMINATION OF THE PROPORTIONS OF a AND 3 EPIMERS IN COMMERCIAL SAMPLES OF CALCIUM GLUCOHEPTONATE 36 2.8 DETERMINATION OF THE PROPORTIONS OF a AND 3 EPIMERS IN THE PRECIPITATE OBTAINED FROM COMMERCIAL SAMPLES OF CALCIUM GLUCOHEPTONATE 38 3. RESULTS AND DISCUSSION 39 3.1 STABILITY STUDIES OF CALCIUM GLUCOHEPTONATE SOLUTIONS 39 3.2 CHARACTERIZATION OF CALCIUM GLUCOHEPTONATE AND THE PRECIPITATE OBTAINED FROM SOLUTIONS OF CALCIUM GLUCOHEPTONATE 39 - viii - Page 3.2.1 Elemental analysis 39 3.2.2 Thermal analysis 39 3.2.3 IR spectra 42 A. Solid samples 42 B. Solutions 47 3.2.4 Heat of solution 47 3.2.5 X-ray diffraction studies 47 3.2.6 Equilibrium solubility 53 A. Calcium glucoheptonate 53 B. Precipitate dried under vacuum at room temperature to constant weight 53 C. Precipitate dried under vacuum at 80°C for 46 hours 54 3.3 IDENTIFICATION OF THE PRECIPITATE 54 3.4 POSSIBLE REASONS FOR PRECIPITATION 55 3.4.1 Change from an unstable form to a stable form 55 3.4.2 Presence of seed crystals inducing crystallization 56 3.4.3 Differing proportions of the a and p! epimers in the calcium glucoheptonate from various sources 57 3.4.4 Some comments about USP specifications of calcium glucoheptonate 60 PART B - DEVELOPMENT OF ORAL AND PARENTERAL LIQUID DOSAGE FORMS CONTAINING CALCIUM GLUCOHEPTONATE 1. INTRODUCTION . 63 2. EXPERIMENTAL 64 2.1 MATERIALS 64 - ix - Page 2.2 DEVELOPMENT OF ORAL FORMULATIONS 65 2.2.1 Basic formula 65 2.2.2 Use of sugar 65 2.2.3 Use of stabilizing agent 65 2.2.4 Method of preparation of oral formulations 68 2.3 DEVELOPMENT OF PARENTERAL FORMULATIONS 70 2.3.1 Basic formula 70 2.3.2 Use of stabilizing agents 70 2.3.3 Method of preparation of parenteral formulations 70 3. RESULTS AND DISCUSSION 3.1 STABILITY STUDIES OF ORAL FORMULATIONS 71 3.2 STABILITY STUDIES OF PARENTERAL FORMULATIONS 71 3.2.1 Sterilization by autoclaving 71 3.2.2 Sterilization by filtration 71 SUMMARY 76 REFERENCES 78 - X - LIST OF TABLES Table Page I .
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