Solid-State Phase Transition Mechanism and ... - ACS Publications

Subscriber access provided by TUFTS UNIV

Article

Solid-state Phase Transition Mechanism and Physical–Chemical Study of the Crystal Forms of Monosodium Alendronate: Trihydrate versus Anhydrate Edeilson V. Gonzaga, André L. M. Viana, Olímpia M. M. S. Viana, and Antonio C. Doriguetto Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01064 • Publication Date (Web): 18 Oct 2016 Downloaded from http://pubs.acs.org on October 19, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Crystal Growth & Design is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Solid-state

Phase

Transition

Mechanism

and

Physical–Chemical Study of the Crystal Forms of Monosodium

Alendronate:

Trihydrate

versus

Anhydrate Edeilson V. Gonzaga,†,§ André L. M. Viana,‡ Olimpia M. M. S. Viana,†,§ Antonio C. Doriguetto*,§

†

Núcleo de Controle Qualidade de Fármacos e Medicamentos, Faculdade de Ciências

Farmacêuticas, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil ‡

Laboratório Central de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade

Federal de Alfenas, Alfenas, Minas Gerais, Brazil §

Laboratório de Cristalografia, Instituto de Química, Universidade Federal de Alfenas, Alfenas,

Minas Gerais, Brazil

Supporting Information

Keywords: Sodium alendronate. Interconversion phases. Polymorphism. Flame photometry. Intrinsic dissolution. ABSTRACT Alendronic acid is one of the most effective diphosphonate compounds used for clinical treatment of bone disorders. It is administered orally as its monosodium salt, for which hydrate and anhydrous crystal forms are known. The monosodium alendronate trihydrate form

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(NaH4A·3H2O) is incorporated into medicines as the Active Pharmaceutical Ingredient (API). The NaH4A·3H2O form can be dehydrated at temperatures above 115 °C, resulting in the anhydrous form (NaH4A). Although the crystal structures of both forms have already been reported, an investigation of the reversible dehydration/hydration solid-phase transition is presented here for the first time. A solid-state mechanism for the phase transition, which involves the reversible dehydration-hydration of the NaH4A·3H2O and NaH4A forms, is also proposed. A systematic study comparing the equilibrium solubility and discriminatory intrinsic dissolution of the NaH4A·3H2O and NaH4A forms is included. To achieve this goal, an alternative method of quantifying alendronate anions released from the crystal forms into solution, flame photometry, is proposed and validated. The stability and interconversion of the NaH4A·3H2O and NaH4A forms are probed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy - attenuated total reflectance (FTIR-ATR), and powder X-ray diffraction (PXRD). 1

INTRODUCTION Diphosphonate (or bisphosphonate) compounds (Figure 1a) are commonly used in the

treatment of bone diseases, e.g., osteoporosis, bone metastasis, and Paget’s disease.1-5 Their action mechanism is directly linked to the ability to specifically inhibit the bone resorption process mediated by osteoclasts and to easily fix the bone matrix.4,6-9 The scientifictechnological importance of diphosphonate anions has motivated several coordination chemistry,10-17 structural,18-30 and crystal engineering31-38 studies of this class of compounds. Alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (Figure 1a), is considered to be the most effective diphosphonate for the clinical treatment of bone disorders.39 It is administered orally as its monosodium alendronate salt, which is highly soluble in water40-41 and practically insoluble in organic solvents.42,43 The drug was approved by the FDA in 1996 under the original brand name of FosamaxTM;44 this Active Pharmaceutical Ingredient (API) is


Page 2 of 35

Page 3 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


currently incorporated into several oral solid-dosage formulations under several brand names, e.g., Adronat, Alendros, Bonalon, Dronal, Fosamax, and Onclast. Alendronic acid (H5A) has a total of six functional groups that may be ionized:45 five H+ donors (four POH groups and one geminate OH group) and one amino group as a H+ acceptor (Figure 1a). Therefore, in theory, seven pH-dependent species are possible in solution: one cationic (H6A+), one neutral/zwitterionic (H5A0,+/-), three anionic/zwitterionic (H4A-,+/-, H3A2-,+/-, H2A3-,+/-) and two anionic (H1A4- and A5-) (Figure 1b). Dissociation of the geminal OH group (at the R2 position, Figure 1a), including H5A, of bisphosphonates in aqueous solutions has not been observed experimentally at least up to pH 13;46 and its pKa6 is thus unknown. The dissociation of the cationic species H6A+, leading to the neutral zwitterion form H5A0,+/- (pKa1 = 1.33), has been reported47 despite its minor presence in the equilibrium state H5A.45 The first work presenting the dissociation constants of H5A is dated at the end of the 1970,48 which are reproduced by referral databases such as the Merck Index43 despite the existence of further references.5,45-47,49-53 The values present in a more recent work are:46 pKa2 = 2.24(1), pKa3 = 6.38(3), pKa4 = 10.68(6) and pKa5 = 11.4(2). Therefore, at the physiological pH (6–8) of the small intestine, the predominate species is H3A2-,+/- (pH > 6.38) or H4A-,+/- (pH < 6.4).

Figure 1 – (a) Formulas of diphosphonate (general formula) and alendronic acid (H5A). (b) pHdependent species of H5A in solution. ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

In terms of crystal forms, monosodium alendronate has been observed in an anhydrous state54,55 and in at least twelve hydrated forms.56-59 However, only two of the reported crystal forms exhibit crystal structures that have been determined thus far: a trihydrate56,57 and an anhydrate,55 which hereafter will be termed NaH4A·3H2O and NaH4A, respectively. It is important to emphasize that NaH4A·3H2O is the crystal form known to be present in the commercial solid-dosage formulations of monosodium alendronate,60 and the NaH4A form can be obtained from the NaH4A·3H2O form by heating it above 115 °C.55 Both the NaH4A and NaH4A·3H2O forms exhibit H4A-,+/- (anionic/zwitterionic species) as a Na+ counter-ion.55-57 However, the neutral zwitterion (H5A0,+/-) and the divalent anion zwitterion (H3A2-,+/-) species have also been observed in the solid state for other H5A and alendronate salt forms. H5A0,+/- is present in two known non-salt crystal structures: the monohydrate61 and anhydrate62 forms of H5A. The structure of alendronate calcium monohydrate was the first reported structure having the H3A2-,+/- anion.63 More recently, Deacon et al. (2015)57 have published a very interesting crystal engineering work involving several coordination polymers of alkali metal cations with alendronate anions. Several crystal forms varying either cations (Na+, K+, Rb+, Cs+) or alendronate species (H4A-,+/- or H3A2-,+/-) were discussed in terms of coordination, hydration level, supramolecular interactions, and dimensionality.57 Emphasis should be given to the pentahydrate disodium alendronate form ([Na2(H3A)(H2O)4]·H2O),57 the anion of which (H3A2-,+/-) is the dominant species at physiological pH (6-8).5 Even though it is well accepted that the knowledge of crystal structures of the different crystal forms of API provides an opportunity for exploring the relationship between structure and properties, there has been no systematic study comparing the crystal forms of H5A or its monoand disodium salts in terms of their equilibrium solubility, dissolution profile, and intrinsic dissolution. There is a study aimed at testing the bioequivalence of monosodium alendronate tablets in vitro and in vivo and describing a mode for evaluating the pharmaceutical quality of


Page 4 of 35

Page 5 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


diphosphonate oral formulations.64 Alendronate ions are immediately released into solution when tablets containing monosodium alendronate come into contact with water. Tablet dissolution starts during deglutition, and the fast release exhibits a potential health risk since it may induce esophagitis.65-66 This concern was addressed in a work that determined the in vitro release of this API from monosodium alendronate tablets of different brands during deglutition.67 It was concluded that in the early stage of dissolution, which covers the time interval of oral intake, generic products released significantly lower amounts of alendronate than the original brand. In this way, the authors argued that the potential health risk from all tested generic products during oral intake is lower than that from the original product. To the best of our knowledge, the impact of different H5A/alendronate crystal forms on the solubility of this API is only mentioned by Ezra and Golomb5, in which the authors argued that the various crystal forms of H5A/alendronate are remarkably different in terms of solubility. The reported solubility values for the H5A monohydrate, NaH4A·3H2O, and NaH4A forms are 8, 300, and 40 g L-1, respectively.5 Therefore, since drug solubility can affect its bioavailability,68-69 it is important to know the exact pharmaceutical formulation by paying attention to the different solid forms. Following our ongoing research to establish the correlation between crystal structures and physicochemical properties of APIs,70-84 the present work aims, firstly, to compare the equilibrium solubilities and intrinsic dissolution profiles of the NaH4A·3H2O and NaH4A forms. Since H5A/alendronate possesses no chromophore, making it difficult to measure by conventional spectrophotometric methods,85-92 we were also motivated to develop an alternative indirect method for its quantification using emission atomic spectroscopy to measure the concentration of Na+. Finally, a solid-state mechanism for the phase transition involving the reversible dehydration-hydration of the NaH4A·3H2O and NaH4A forms is proposed here for the first time.

2

EXPERIMENTAL SECTION



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2.1 SAMPLES

Monosodium alendronate raw materials were acquired from two different suppliers and were coded as raw materials I (supplied by Gemini Goiás, Brazil, batch SA/15/11) and II (supplied by Galena, São Paulo, Brazil, batch SA/08/10), the origin of which was not provided by the supplier. Both samples were identified, using powder X-ray diffraction (PXRD) methods, as the NaH4A·3H2O form. To obtain high-purity polycrystalline samples of NaH4A·3H2O, raw material II was dissolved in a 1.5:1.0 (v/v) methanol:water mixture. After a filtration procedure to eliminate impurities/undissolved materials, the solution was maintained at 25 °C in the absence of vibrations and light. The crystalline material, which formed after two days, was separated from the remaining solution by filtration and was characterized by PXRD as being the NaH4A·3H2O form. Approximately 300 mg of the recrystallized NaH4A·3H2O form was slowly heated to 150 °C and kept at this temperature for 1 h.55 Then, the material was cooled to room temperature and immediately characterized by PXRD, confirming the NaH4A form.

2.2 POWDER X-RAY DIFFRACTION ANALYSIS

PXRD data were recorded at room temperature (293 K) using an Ultima IV diffractometer (Rigaku, Tokyo, Japan) with θ–2θ geometry. CuKα radiation (λ = 1.5418 Å) was generated using a sealed tube at 40 kV and 30 mA. The data were collected with a step size of 0.02° in 2θ. The speed of scanning was 1° 2θ / min., from 3 to 35° in 2θ. The samples were finely ground and mounted on a grooved glass slide employed as a sample holder. The experimental PXRD patterns were compared with those calculated by importing the crystal structures determined for


Page 6 of 35

Page 7 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the NaH4A (CCDC code: UTOKAQ)55 and NaH4A·3H2O (CCDC code: TEHWOS)56 forms into MERCURY.93

2.3 INFRARED SPECTROSCOPY ANALYSIS

Fourier transform infrared spectroscopy - attenuated total reflectance (FTIR-ATR) spectra were obtained using an Affinity-1 Fourier transform infrared spectrophotometer (Shimadzu, Tokyo, Japan) coupled to a PIKE Miracle attenuated total reflectance sampling accessory with ZnSe waveguides (PIKE Technologies, Wisconsin, USA). Spectra were recorded at room temperature using 32 scans and a resolution of 4 cm-1 over the range from 4000-600 cm-1.

2.4 THERMAL ANALYSIS

Differential

scanning

calorimetry

(DSC)

curves

were

obtained

on

a

DSC Q20 V24.11 Build 124 unit (TA Instruments, New Castle, USA) under a dynamic atmosphere of nitrogen (50 mL min-1) with a heat flow of 10 °C min−1 from 35 to 500 °C using open aluminum crucibles with approximately 2 mg of sample. The instrument was calibrated with an indium standard. Thermogravimetric analysis (TGA) curves were obtained on a SDT Q600 V20.9 Build 20 unit (TA Instruments, New Castle, USA) using open aluminum crucibles, a heating rate of 10 °C min-1 from 35 to 500 °C, a nitrogen flow of 50 mL min-1, and approximately 12 mg of sample.

2.5 INTERCONVERSION STUDIES



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The possibility of a reversible phase transition due to the rehydration of the NaH4A form was also studied by exposing it to environments containing water. Three environments were tested: a) an aqueous saturated solution was prepared from the NaH4A form obtained here, followed by immediate separation of the solid phase in equilibrium by filtration; b) a volume of distilled water (50 µL) sufficient to moisten a given mass (200 mg) of ground NaH4A was added to fill the grooved glass slide employed as a sample holder in the PXRD experiment; c) approximately 100 mg of the NaH4A form was placed in a climatic chamber at 40 °C with 75% relative humidity for 12 h. The PXRD patterns were recorded immediately after the end of the three sample wetting procedures described above.

2.6 SODIUM ALENDRONATE QUANTIFICATION METHOD

H5A does not possess chromophore groups that can absorb sufficiently in the UV-VIS spectral range to permit its quantification using conventional spectrophotometric techniques.92 Thus, several studies of sodium alendronate determination use derivatization reactions for spectrophotometric quantification in both tablets and raw materials.85-91 Therefore, the official chromatographic method using a UV-VIS detector for the quantification of sodium alendronate described in the United States Pharmacopoeia60 requires a long analysis time due to the need for derivatizing procedures. Another disadvantage is the use of an expensive derivatizing reagent, namely, 9-fluorenylmethyl chloroformate. In addition, elution of the mobile phase is carried out in gradient mode with ~32 minutes of running time per sample. The column used for separation is L21, an unusual column with a stationary phase consisting of a divinylbenzene styrene copolymer.60 Therefore, here we propose an alternative method to indirectly quantify the amount of alendronate species in aqueous media by measuring the Na+ concentration (1:1 counter-ion to alendronate anion in the monosodium alendronate crystal forms) by flame photometry. This


Page 8 of 35

Page 9 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


method can only be applied, of course, to samples containing no other sources of Na+ cations besides those of the alendronate crystal forms. A flame photometer, model FC-280 (CELM – São Paulo, Brazil), was used in the analysis. Ultrapure water (Milli-Q, Merck Millipore, Germany) was used as the equipment blank. A commercial standard solution (FC-280) of 140 mmol L-1 Na+ was used to calibrate the photometer. Solutions of 32.5 µg mL-1 (0.100 mmol L-1) of Na+ were prepared from NaH4A·3H2O in ultrapure water to calibrate the equipment response. The method was validated according to the specifications of resolution number 899 of the Brazilian Health Surveillance Agency (ANVISA) in 2003 and the Q2B guidelines of the International Conference on Harmonization (ICH).94,95 The evaluated parameters were linearity, precision, accuracy, selectivity, and the limits of detection and quantification. The results of the validation can be found in the Supporting Information (Section S1).

2.6.1 Linearity

To assess the linearity, an analytical curve was recorded using five solutions prepared from the recrystallized NaH4A·3H2O form at concentrations of 20, 80, 200, 280, and 400

µg mL-1, corresponding to 0.0615, 0.246, 0.615, 0.861, and 1.23 mmol L-1 of Na+ ions, respectively. Due to the equimolarity ratio of alendronate- and Na+ in solution, the analytical curve can be applied to solutions prepared from both the NaH4A·3H2O and NaH4A forms to indirectly calculate the total amount of A species in the studied samples. This range was chosen to encompass the range from 5 to 100% of drug release (w/w) for the intrinsic dissolution test. The linearity results are presented in the Supporting Information (Section S1, Table S1).

2.6.2 Precision



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 35

A solution of known concentration (0.615 mmol L-1) of sodium alendronate was read on the flame photometer six times on the same day (intra-day n = 6) and six times on another day (inter-day n = 12). The relative standard deviation (RSD) was calculated for intra- and inter-day analyses. The precision results are presented in the Supporting Information (Section S1, Table S2).

2.6.3 Accuracy

To evaluate the method accuracy, readings were acquired for blanks (ultrapure water) and standards (0.0615, 0.615, and 1.23 mmol L-1 of Na+ ions). The RSD and percentage of recuperation (%E) were calculated from the measured values. The accuracy results are in the Supporting Information (Section S1, Table S3).

2.6.4 Selectivity

The selectivity was checked using lithium and potassium chloride aqueous solutions prepared to have the same concentrations as those used to test linearity (0.0615 mmol L-1 to 1.23 mmol L-1 of Li+ or K+ ions). The selectivity results are presented in the Supporting Information (Section S1).

2.6.5 Detection and quantification limits

The detection limit (DL) and quantification limit (QL) were obtained from Eqs. (1) and (2), respectively:

=

σ


(1)

Page 11 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


=

σ

(2)

where σ is the intersection standard deviation and S is the slope of the calibration curve obtained in the linearity study. The detection and quantification limit are in the Supporting Information (Section S1).

2.7 SOLUBILITY STUDY

The solubilities of NaH4A and NaH4A·3H2O at equilibrium were individually determined in different aqueous media using the equilibrium method.96 Five aqueous media (Na+-free) were used to determine the equilibrium solubilities in accordance with Resolution Number 031/2010 and Technical Note Number 003/2013,96,97 namely, ultrapure water; 0.01 mol L-1 HCl, pH 3.5 (15.6 mol L-1); and pH 6.0 (2.73 mol L-1) and pH 7.2 (4.78 mol L-1) acetate buffers. The NaH4A and NaH4A·3H2O forms were sieved and individually placed in 30 mL flasks containing 15 mL total volume of each medium under study. The solutions were prepared in triplicate. They were vortexed until the formation of a residual solid material at the bottom of the flask. The flasks were agitated at 150 rpm and 25 °C over 48 h on a shaker table, model SL 180 DT (SolabTM, São Paulo, Brazil). After the stirring process, the samples were filtered through a PTFE syringe filter (filter diameter of 13 mm and pores of 0.45 µm), and the final pH of each solution was measured. The concentration of the H5A species in each solvent was determined by the alternative method proposed in this work, flame photometry (Section 2.6). The residual solids obtained from filtration of the undissolved solid materials in equilibrium with the solution were dried in a desiccator containing silica for 7 days, followed by PXRD analysis to verify if the resulting material was the same as the starting material.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2.8 DISCRIMINATORY INTRINSIC DISSOLUTION STUDY

The intrinsic rates of dissolution of the NaH4A and NaH4A·3H2O forms were determined using discs with a constant surface area (0.5 cm2), which were prepared by pressing the samples (200 mg) for 1 minute using a hydraulic press (1 kN). The Discriminatory Intrinsic Dissolution (DID) study was performed under the following conditions: 500 mL of the dissolution medium at 37 °C (a buffer pH of 6.0 (2.73 mol L-1) was chosen, taking into account the equilibrium solubility results), and a rotating disc was used as the apparatus, with sampling times of 3, 5, 7, 15, 30, and 60 min. The sampling volume withdrawn at each time was 10 mL, followed by immediate dilution to the original volume. All collected aliquots were filtered through a PTFE filter with a porosity of 0.45 µm, and the amount of H5A species released into solution was quantified by determining the sodium content by flame photometry (Section 2.6).

3 RESULTS AND DISCUSSION

3.1 SAMPLE CHARACTERIZATION

A comparison of the calculated PXRD patterns of the NaH4A55 and NaH4A·3H2O56 forms with the experimental patterns of raw materials I and II reveals that both commercial samples contained only, or at least mostly, the NaH4A·3H2O form (Figure S1, Supporting Information). It can also be concluded that the procedures to obtain the recrystallized NaH4A·3H2O form as well as heating the recrystallized NaH4A·3H2O form at 150 °C for 1 h to produce the NaH4A form were successful (Figure S1, Supporting Information). These results were corroborated by FTIR-ATR (Section S2, Figures S2, Supporting Information), DSC, and TGA (Section 3.2, Figures 1 and 2; and Section S2, Figure S4, Supporting Information) analyses.


Page 12 of 35

Page 13 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3.2 REVERSIBLE DESOLVATION/SOLVATION BEHAVIOR

The DSC curve of the NaH4A·3H2O form exhibits two sharp endothermic peaks, with the highest peak areas at approximately 123 and 129 °C (Figure 2). These peaks correspond to the dehydration process since the TG curve of the NaH4A·3H2O form (Figure 3) shows a mass loss corresponding to three mol of water molecules per mol of Na-A (∆mTG = 16.5% and ∆mcalc. = 17.2%). The double event associated with the dehydration process shows that the release of non-coordinate and coordinate water molecules present in the crystal structure of the NaH4A·3H2O (Figure S3, Supporting Information) occurs at different temperatures. The two water molecules that are non-coordinated to the sodium cation in the NaH4A·3H2O structure are released first, at 123 °C, whereas the coordinated molecule, which is more strongly bonded to the host structure, is released slightly later, at 129 °C. This hypothesis is corroborated by the TG curve, which shows a dehydration process covering a large temperature range, from 115 to 135 °C, and in two distinct steps, as highlighted by the first derivative of the TG curve (DTG) (see inset in Figure 3). As previously published55 and confirmed in this work, the dehydrated product (NaH4A) is stable up to ~270 °C (Figure 2 and 3), at which point it begins to undergo fusion (endo), immediately followed by decomposition (exo). As expected, no event at approximately 125 °C is observed in the DSC and TG curves (Figure 2 and Figure S4, Supporting Information) of the NaH4A form, confirming that the sample obtained here was completely dehydrated. The TG curve of the NaH4A form shows only the fusion/decomposition events at temperatures above 267 °C (Figure S4, Supporting Information). A cyclic DSC curve of the NaH4A·3H2O form, obtained by the protocol of heating and cooling at approximately the dehydration temperature, is also given in Figure S5 (Supporting Information) and confirms the in-situ dehydration process that leads to the NaH4A form.



NaH4A NaH4A·3H2O

-1

Heat flow (mW.mg )

Endo

267 °C (Fusion) 129 °C (Dehydration) 123 °C 100

200

300

400

500

o

Temperature ( C)

Figure 2 – DSC curves of the NaH4A·3H2O and NaH4A forms. The thermal events associated with dehydration and fusion/decomposition are highlighted.

100 90 Mass (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 35

DTG

80

TG 70 DSC

60 100

100

125

150

200 300 Temperature (°C)

400

500

Figure 3 – TG and DTG (first derivative of the TG) curves for NaH4A·3H2O. The inset is a close-up of the TG and DTG curves from 100 to 150 °C, including the DSC curve (in magenta) given in Figure 2, to highlight the two-step dehydration process at approximately 125 °C.

The experimental PXRD pattern of the NaH4A form exposed to a climatic chamber (12 h at 40 °C with 75% RH) clearly shows the peaks from both the NaH4A and NaH4A·3H2O form, indicating a partial crystal phase conversion (Figure 4). The PXRD patterns from the a) and b)


Page 15 of 35

wetting procedures described in Section 2.5 show that the original NaH4A form was completely converted to NaH4A·3H2O. These results indicate that NaH4A can be easily reconverted to NaH4A·3H2O through an instantaneous process in the presence of liquid water. No evidence of the hydrate disodium alendronate form (Na2H3A·5H2O)57 is observed.

Moisten Normalized Intesity (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Water equilibrium Climatic chamber NaH4A·3H2O Calc. NaH4A Calc. Na2H3A·5H2O Calc. 5

10

15 20 Degree 2θ (CuKα)

25

30

Figure 4 – Experimental PXRD patterns of the NaH4A form after incubation in the three moist environments described in Section 2.5. The calculated PXRD patterns from the crystal structures reported for the NaH4A,55 NaH4A·3H2O56 and Na2H3A·5H2O 57 forms are also included.

3.3 REVERSIBLE DESOLVATION/SOLVATION MECHANISM

Taking into account the reversible hydration/dehydration solid-state phase transition observed for the NaH4A·3H2O and NaH4A forms, this section presents insights concerning the



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

adsorption/desorption mechanism by combining structural information and thermal analysis (Section 3.2, Figures 3, 3; Section S2, Figure S4, Supporting Information). Although the crystal structures of both the NaH4A·3H2O and NaH4A forms have already been determined55,56, to the best of our knowledge, an investigation of the phase transition mechanism is provided here for the first time. To compare the two structures, selected crystallographic parameters reported for the NaH4A55 and NaH4A·3H2O56 forms are compiled in Table S4 (Section S3, Supporting Information). Their respective TEHWOS and UTOKAQ CIF files, obtained from the Cambridge Structure Database (CSD),98 were used to generate the artwork presented here using the programs MERCURY93 and OLEX2.99 It is important to emphasize that only intra- and intermolecular features relevant to the phase transition mechanism are discussed here. Other crystal structural details concerning the two structures require access to the reported data.55,56 Figure 5 shows that the NaH4A and NaH4A·3H2O crystal structures have a common supramolecular synthon formed by their respective asymmetric units that is operated by the 21fold screw axis of the monoclinic P21/n space group, which is also common to the two structures (Section S3, Table S4, Supporting Information). This supramolecular building block generates, by translation, a zig-zag chain that is quite similar along the respective unit cell b axis to the perpendicular 4-aminobutylidene groups.55,56 In fact, the comparability of the b axis of the unit cells of the NaH4A (9.1458(7) Å)55 and NaH4A·3H2O (9.002(2) Å)56 forms is a direct consequence of the chain similarity. However, as previously discussed by Asnani et al. (2009),55 the packing arrangements of molecules in the NaH4A and NaH4A·3H2O forms are markedly different. The NaH4A·3H2O form is a 1-D Coordination Polymer (CP) (Figure 5a), whereas the NaH4A form is a 2-D CP (Figure 6). It can be noted in Figure 5a that the octahedral coordination sphere of the sodium cation in the NaH4A·3H2O form is completed by one water molecule. The hydration, in this case, can be correlated to the formation of the 1-D CP, since the NaH4A form obtained by heating of NaH4A·3H2O (see Section 3.1) is a 2-D CP formed by edge-shared sodium polyhedra (Figure 6). This means that the parallel zig-zag chains in NaH4A


Page 16 of 35

Page 17 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


are themselves linked through the oxygens marked by asterisks in Figure 5b, giving rise to the 2-D CP shown in Figure 6.

Figure 5 – Views of the zig-zag chains along the b axes of the unit cells of the crystal structures of the NaH4A·3H2O (a) and NaH4A (b) forms. The dashed black circles highlight the common supramolecular synthon of these structures. In (a), the oxygen atoms of water that are coordinated to the sodium cations are identified. In (b), the phosphonyl oxygen atoms that are shared by neighboring chains to form the 2-D CP (See Figure 6) of the NaH4A form are marked by asterisks. The NaH4A·3H2O and NaH4A chains shown in (a) and (b) are also projected down their respective crystallographic b axes ((c) and (d)), highlighting that the 4-aminobutylidene groups are oriented normal to the direction of chain growth. Hydrogen atoms are omitted for clarity.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 6 – The 2-D CP of the NaH4A form, as viewed down the unit cell a axis. The phosphonyl oxygen atoms participating in the edge-shared sodium octahedra are indicated by dashed black circles. Hydrogen atoms are omitted for clarity.

Figure 7 presents the packing of the NaH4A·3H2O and NaH4A forms projected onto their respective ac planes, showing how the chains parallel to their respective unit cell b axes (Figure 5) are assembled. For the NaH4A·3H2O form, which is a 1-D CP, the chains of the first neighbor are stacked along the [100] and [101] directions (Figure 7a). Least squares planes through the sodium cations of chains stacked along [101] were calculated, highlighting a layered structure parallel to the crystallographic (-101) plane. The layers can be separated into two sets: the set containing the 4-aminobutylidene groups (A layers) is delineated by neighboring planes separated by 3.214 Å, whereas the set containing the coordination and hydration water molecules (B layers) is defined by neighboring planes separated by 3.930 Å (Figure 7a). A very similar layered structure is observed for the NaH4A form (Figure 7b). The calculated least squares planes through the sodium atoms of the chains stacked along the [-101] direction highlight this structural similarity, and once again, the layered structure can be separated into two sets. As for the NaH4A·3H2O form, one set contains 4-aminobutylidene groups (A layers) with the analogous planes separated by 3.658 Å (slightly longer than that observed in the NaH4A·3H2O ACS Paragon Plus Environment

Page 18 of 35

Page 19 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


form). In contrast to the NaH4A·3H2O form, the B layers in the NaH4A form are water-free and contain the oxygens of edge-shared sodium octahedra. Consequently, the width of the B layer in the NaH4A form is significantly reduced to 1.769 Å, a value less than half of that calculated for the NaH4A·3H2O form (3.930 Å). Figure 7b also shows that the NaH4A form has its 2-D coordination polymer sheets stacked parallel to the (-101) plane.

(a)

(b) Figure 7 – Packing view of the NaH4A·3H2O (a) and NaH4A (b) forms on their respective ac planes. The chains stacked along the horizontal line are arbitrarily colored in yellow and green. The sodium atoms are shown as yellow/green spheres, and water oxygen atoms in (a) are shown as red spheres. Least squares planes through the sodium cations are in blue. The labels A and B



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

are used to differentiate the two sets of layers (see discussion) present in each structure. The inter-planar distances are included. The two possible directions ([100] or [301], dashed black boxes in (a)) in which the NaH4A·3H2O crystal structure could be interconnected to form the NaH4A structure are given, highlighting that the linkage occurs along the [301] direction (ticked direction), not [100], giving rise to the 2-D CP sheets (dashed black box in (b)) parallel to the (101) plane of the NaH4A crystal structure.

As expected, the void volume (calculated by MERCURY93 using the contact surface approach with grid spacing and a probing-sphere radius of 0.7 and 1.1 Å, respectively) occupied by the hydration water molecules (136.70 Å3, 10.9%) of the unit cell of the NaH4A·3H2O form lies in the B layer, confirming its channel solvate feature (Figure 7a and Section S3, Figure S6, Supporting Information). If the coordinated water molecule is also considered, the void volume is only slightly increased to 141.72 Å3 (11.3%). It is important to remember that the thermal analyses show that the dehydration process takes place in two stages, first releasing the two water molecules that are non-coordinated to the sodium cation and then releasing the coordinated water molecule. It is important to quantify the void volume (defined as empty spaces in the crystal unit cell that are large enough to hold a spherical “probe” of the given radius93) to explain the water adsorption/desorption of crystalline materials, which may be of three types: the crystal structure can undergo i) no or little change, ii) a reversible change or iii) an irreversible change. Channel solvates with void volumes greater than 10%, as in the NaH4A·3H2O form, are expected to collapse upon solvent removal,100 which is in agreement with the adsorption/desorption of the NaH4A·3H2O and NaH4A forms, followed by changes in the crystal structure.55 The void volume of the NaH4A·3H2O form is also correlated with the decrease (26%) of the unit cell volume (from 1255.4 to 931.4 Å3) and with the increase (12%) of the unit cell density (from 1.720 to 1.933 mg cm-3) when it is dehydrated above 115 °C to yield the NaH4A form. Formation of the


Page 20 of 35

Page 21 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


fused-edge-shared sodium octahedra also contributes to the above-mentioned trends when the NaH4A·3H2O form is transformed to the NaH4A form. Finally, we analyzed the reversible mechanism of water adsorption/desorption involving the NaH4A·3H2O and NaH4A forms. As shown above, it is clear that the water molecules leave the crystal structure of the NaH4A·3H2O form through the channels parallel to the b axis of the unit cell (Figure 7a and Section S3, Figure S6, Supporting Information). The challenge now lies in understanding how the sodium octahedra of neighboring B layers are fused, leading to the edge-shared octahedra in the NaH4A form. A careless comparison could lead us to propose that the direction of chain linkage in the NaH4A·3H2O form is [100] (Figure 7a). However, this is forbidden since the chains stacked along [100] are related by translation along the a axis and the 21-fold screw symmetry axis along the b axis of the unit cell. This means that the linkage of chains along [100] (yellow + green, Figure 7) makes it impossible for the phosphonyl oxygen atoms to bridge adjacent sodium octahedra to form the centrosymmetric edge-shared octahedra observed in the NaH4A form (Figure 8). Therefore, the real linkage direction (Figure 7a) is parallel to [301] (yellow + yellow and green + green), through the chains related by the inversion symmetry of the P21/n space group.

Figure 8 – Polyhedral representation of the NaH4A·3H2O and NaH4A forms, showing neighboring inter-chain sodium octahedra related by inversion symmetry (right), which are necessary for the formation of centrosymmetric edge-shared octahedron dimers (left).



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Section S3, Figure S7 (Supporting Information) is a packing representation with alternative unit cells of the NaH4A·3H2O and NaH4A forms, with either the b or c axis lying in the least squares planes through the sodium atoms, as shown in Figure 7. These new choices better highlight the impact of the solid-state phase transition on the unit cell volume and density. The a and b axes of the alternative unit cells, as well as their respective volumes and densities, are equal to those of the original unit cells (Section S3, Table S4, Supporting Information). The alternative c axis and β angles are 19.520 Å and 79.12°, respectively, for the NaH4A·3H2O form and 18.762 Å and 134.65°, respectively, for the NaH4A form. Therefore, the phase transition impacts the β angle more significantly than the axis of the alternative unit cell, which is clearly depicted in Section S3, Figure S7 (Supporting Information). This is a consequence of the release of water molecules through the channels parallel to the unit cell b axis, followed by the sliding of neighboring layers. In addition to the horizontal sliding, neighboring layers are also drawn closer to each other. The two concomitant movements link inter-layer chains related by inversion symmetry (green + green and yellow + yellow) (Section S3, Figure S7, Supporting Information). The inverse movement occurs during hydration. Figure 9a shows a triad of chains of the NaH4A·3H2O and NaH4A forms viewed on their respective ac planes. The same triads are projected onto the (-301) and (100) planes of the NaH4A·3H2O and NaH4A forms, respectively (Figure 9b), to illustrate the filling of channels by water molecules and the parallel chain displacement during the water adsorption/desorption process. Taking the inter-chain neighboring sodium cations as a reference, the cation-cation distance is reduced from 11.429 to 3.568 Å (a gap of 7.861 Å) during desorption and vice-versa during adsorption. Interestingly, the adsorption/desorption process can be compared to a zipper function, with the water input/output as its open-close mechanism (Figure 9b); it can be opened and closed by wetting and heating, respectively.


Page 22 of 35

Page 23 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(a)

(b) Figure 9 – (a) Packing view of triads of chains of the NaH4A·3H2O and NaH4A forms viewed on their respective ac planes and showing the magnitude of chain displacement during the adsorption/desorption process. (b) The same triads projected onto the (-301) and (100) planes of the NaH4A·3H2O and NaH4A forms, respectively, depicting the inter-chain Na-Na distances.

3.4 SOLUBILITY STUDIES

Figure 10 (see values in Section S4, Table S5, Supporting Information) compares the equilibrium solubility values of the NaH4A and NaH4A·3H2O forms in five different media to account for the physiological pH range. The final pHs at equilibrium (Section S4, Table S5, Supporting Information) were almost invariant for the same medium. The final pHs of solutions ACS Paragon Plus Environment


containing 0.01 M HCl and water as media were, respectively, higher (~3.6) and lower (~4.2) than the initial pHs. Both changes are due to the amphoteric behavior of the alendronate H4A-,+/species released into solution from the sodium alendronate crystal forms. For the remaining buffered media, the differences between the initial and final pH were less significant. 100 NaH4A

90 -1

Solubility (g L )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 35

NaH4A·3H2O

80 70 60 50 40 30 1M 0.0 l HC

pH

ter 6.0 Wa pH Dissolution Media

3.5

7 pH

.2

Figure 10 – Equilibrium solubility values for the NaH4A and NaH4A·3H2O forms at 25 °C, 150 rpm, and 48 h in different media (water, 0.01 M HCl, and buffer solutions with pH 3.5, 6.0, or 7.2). Error bars represent standard deviation. The final pH at equilibrium is given in Table S5, Supporting Information. Before discussing the equilibrium solubility values, it is first necessary to consider which crystal form is in equilibrium with the saturated solution at the end of the experiment. The experimental PXRD patterns of the residual solid materials separated from the solutions (Section S4, Figure S7, Supporting Information) show that the stable crystalline form of alendronate in all media is NaH4A·3H2O, irrespective of the starting crystal form (NaH4A·3H2O or NaH4A). This means that the NaH4A form undergoes conversion to NaH4A·3H2O one during the equilibrium solubility experiment. This is an expected behavior, considering the results discussed in Sections 3.2 and 3.3; it is also expected that the NaH4A form will have only a slightly higher equilibrium solubility (by mass proportion) than NaH4A·3H2O and that it is not as drastically different as that observed in the study (Figure 10). Indeed, the greater solubility of the NaH4A form, observed here in all media, may be explained by its supersaturation with respect to the solubility ACS Paragon Plus Environment

Page 25 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of NaH4A·3H2O. This atypical behavior is a probable consequence of slow nucleation and/or crystal growth during the interconversion of NaH4A to NaH4A·3H2O in aqueous solutions, as previously observed, e.g., for doxycycline101,84 and orbifloxacin.83 Interestingly, comparing the NaH4A·3H2O (33.70 ± 0.68 g L-1, final pH = 4.22) and NaH4A (35.97 ± 0.68 g L-1, final pH = 4.27) forms in the same medium, the closest equilibrium solubility values are observed in water. While the value published for NaH4A·3H2O (40 g L-1) in by Ezra and Golomb5 is comparable to that obtained here, the published value for NaH4A (300 g L-1) is much higher. This discrepancy could be associated with the electrolyte effect and/or pH-dependence of the alendronate solubility at equilibrium, as will be discussed later. For the other media, the NaH4A form is significantly more soluble than the NaH4A·3H2O form, reaching a maximum value of 94.81 ± 0.99 in the buffer medium with pH = 3.5 (final pH = 3.23). The highest variation (30.34%) was observed when comparing the NaH4A (65.33 ± 2.58 g L-1, final pH = 5.75) and NaH4A·3H2O (42.26 ± 1.72 g L-1, final pH = 5.80) forms in the buffer medium with pH 6.0. Therefore, this medium was chosen as the testing medium for the intrinsic dissolution study discussed in Section 3.5. Since the final pHs at equilibrium (Section S4, Table S5, Supporting Information) vary from 3.2 to 6.3 and because H5A is a polyprotic acid having two acid constants (pKa2 = 2.60(1) and pKa3 = 6.67(1)46 in this pH range, three pH-dependent alendronate species could be formed in solution when the H4A-,+/- ions are released from their crystal forms: H5A0,+/-, H4A-,+/-, and H3A2-,+/- (Figure 1). Considering the distribution diagram of the relative presentation of these three species (Figure 11), H4A-,+/- is expected to be the major species from pH = pKa2 to pH = pKa3, being in equilibrium with H5A0,+/- (pH < 4.3) or H3A2-,+/- (pH > 4.3) (Figures 1, 10 and 11). Since in the water media, the final pHs for both the NaH4A·3H2O or NaH4A forms are very close to 4.3, their solutions are expected to contain almost entirely the H4A-,+/- species.



pH = 4.3

1,0

0,8

Molar Fraction

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 35

-,+/-

H4A

0,6

pKa3 = 6.4

pKa2 = 2.2 0,4 0,+/-

H5A

2-,+/-

H3A

0,2

0,0

2

3

4

5 pH

6

7

8

9

Figure 11 – Equilibrium distribution diagram of the relative abundance of protonated species of alendronate over the final measured pH range. The molar fraction (α) of each species was ,/

calculated as follows: = [ ,/

= [

]/ = (1 + ( /[ ]) + (( × )/[ ] ));

,/

]/ = ( /[ ]);

= ,/

where + + = 1 and =

,/

+ [

/ = (( × )/[ ] );

,/

] +

. A pH step of 0.1

was used to calculate the molar fraction of each species. The remaining pH-dependent alendronate species were omitted from the calculation. The complete distribution diagram (from 0 to 14 and considering pKa2, pKa3, pKa4 and pKa5), which is in agreement with the partial diagram presented here, can be found in Meloun et al.45 Because the final pHs of the media using buffers of pH = 6.0 (final pH ~5.8) and pH = 7.2 (final pH ~6.3) are close to pKa3, the concentration of the H4A-,+/- and H3A2-,+/- species are expected to be equivalent in these media. However, in spite of the very close final pHs, the equilibrium solubility of the NaH4A form in the buffer of pH = 6.0 is twice as high as that in the buffer of pH = 7.2 (Figure 10 and Table S5, Supporting Information). Neutral zwitterionic (H5A0,+/-) and monovalent anion zwitterionic (H4A-,+/-) species are expected to coexist in equilibrium with the solid phase in 0.01 M HCl (final pH ~3.6) or buffer pH = 3.5 (final pH ~3.2) media. Once again, the equilibrium solubility values (now for both forms) are significantly different for the two media (twice as high in buffer of pH = 3.5 than in


Page 27 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.01 M HCl), although they have a similar final pH (Figure 10 and Table S5, Supporting Information). Indeed, there are at least three complicating factors in data interpretation when the equilibrium solubilities of the alendronate forms are compared in different media: i) the coexistence of three different alendronate pH-dependent species in the studied pH range; ii) the observation that different aqueous media (HCl, acetate buffers or pure water) present different electrolyte concentrations (ionic strength) to reach different pHs; and iii) the zwitterionic nature of alendronate in aqueous solution, which can show a positive salt effect even for the neutral specie H5A0,+/-. Therefore, in general terms, it can be only conclusively stated that: i) the lowest equilibrium solubility value, which is found in the pure water medium, is due to the majority presence of the aqueous H4A-,+/- species in equilibrium with the solid form; and ii) the solubility can be increased at pHs either slightly lower or slightly higher than pH 4.3, which could be influenced in part by the conversion of the H4A-,+/- species into H5A0,+/- or H3A2-,+/-.

3.5 DISCRIMINATORY INTRINSIC DISSOLUTION STUDY (DID)

Figure 12 (See also Section S5, Table S6, Supporting Information) shows the intrinsic dissolution curves of the NaH4A and NaH4A·3H2O forms in the acetate buffer medium with pH 6.0. Greater release of the NaH4A form compared to the NaH4A·3H2O form was observed at all sampling times. Considering the curve slopes (1.11(2) and 0.94(3) mg min-1) and the compressed material surface area (0.5 cm2), the intrinsic dissolution rates (IDRs) obtained for the NaH4A and NaH4A·3H2O forms are 2.22(4) and 1.88(6) mg cm-2 min-1, respectively. Therefore, in agreement with the equilibrium solubility study, it is observed that the dissolution rate of the NaH4A form is significantly higher (18%) than that of the NaH4A·3H2O form. Since it is known that the dissolution of sodium alendronate tablets has already started during deglutition, which may induce esophagitis,65-66 the inadvertent presence of NaH4A may potentiate the risk of side



effects for continuous users of this medicine. Fortunately, this small difference is not expected to make a significant difference in the amount of this API dissolved in the esophagus. Moreover, modern pill-coating methods are expected to eliminate early dissolution until the pill is in the stomach.

80

2

y = 1.11(2)x + 13.2(4) R = 0.99862 2 y = 0.94(3)x + 12.0(6) R = 0.99564

70 -1

API Release (mg L )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 35

60 50 40 NaH4A

30

NaH4A·3H2O Linear Fit Linear Fit

20 10 0

10

20

30

40

50

60

Collection Time (min)

Figure 12 – Discriminatory intrinsic dissolution profile graph of the NaH4A and NaH4A·3H2O forms.

4. CONCLUSION

With the prior knowledge that the NaH4A·3H2O form is converted to the NaH4A form by heating, this work showed that the reverse process can be easily induced by exposing the dehydrated form to humid or wetting conditions. The fast hydration process can justify the use of the NaH4A·3H2O form instead of the NaH4A form as a monosodium alendronate API. The void volume (10.9%) occupied by the hydration water molecules in the unit cell of NaH4A·3H2O explains the water desorption associated with the crystal structure change because channel solvates with void volumes >10% are expected to collapse upon solvent removal. The solid-state reversible dehydration/rehydration was explained by analyzing the two crystal structures. In spite of the different crystal structures of NaH4A·3H2O (a 1-D coordination polymer) and NaH4A (a ACS Paragon Plus Environment

Page 29 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2-D coordination polymer), they have common structural features (supramolecular synthon, zigzag chains, layered structure, and channel along the same unit cell axis), which makes the reversible phase transition permissible. It was also shown how non-shared sodium octahedra in NaH4A·3H2O are fused, leading to the edge-shared sodium octahedra in NaH4A. Taking into account the physical–chemical properties of NaH4A·3H2O and NaH4A, it was shown that NaH4A exhibits greater solubility than NaH4A·3H2O in all media, indicating that the NaH4A form is slightly less stable (lower lattice energy) than NaH4A·3H2O. This trend was confirmed by the discriminatory intrinsic dissolution study, which showed that the dissolution rate of the NaH4A form is slightly higher than that of the NaH4A·3H2O form.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI:? Validation of the flame photometry method to determine sodium alendronate. PXRD patterns and FTIR-ATR spectra and TGA and DSC curves. Additional figures and tables for the desolvatation/solvatation mecanism discussion and solubility results (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interests.

ACKNOWLEDGMENTS The authors thank FINEP (ref 134/08), CNPq (552387/2011-8; 308354/2012-5; 448723/2014-0; 308162/2015-3), CAPES (AUX PE-PNPD-2347/2011), and FAPEMIG (APQ-00273-14 and APQ-02486-14) for financial support. We also thank CNPq, FAPEMIG, and CAPES for research fellowships (E.V.G; A.C.D). This work is a collaborative research project by members



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

of the Rede Mineira de Química (RQ-MG), supported by FAPEMIG (Project: CEX-RED-0001014). References

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)

(12) (13) (14)

(15) (16) (17) (18) (19) (20) (21) (22)

Fleisch, H. The Parthenon Publishing Group Inc, New York; 1995. Fleisch, H. Academis Press, San Diego-London, 2000. Lin, J. H. Bone 1996, 18, 75-85. Papapoulos, S. E. Best Pract. Res. Clin. Endocrinol. Metab. 2008, 22, 831–847. Ezra, A. Golomb, G. Adv. Drug Deliv. Rev. 2000, 42, 175–195. Graham, R.; Russell G. Bone 2011, 49, 2–19. Cremers, S.; Papapoulos, S. Elsevier Inc., Bone 2011, 49, 42–49. Marcus, R.; Hardman, J. G.; Limbird, L. E.; Molinoff, P. B.; Ruddon, R. W.; Gilman, A. G. McGraw-Hill: Rio de Janeiro, 1996, 61. Fleisch, H. Endocr. Ver. 1998, 19, 80–100. Compain, J. D.; Mialane, P.; Marrot, J.; Secheresse, F.; Zhu, W.; Oldfield, E.; Dolbecq, A. Chem.: A Eur. J. 2010, 16, 13741-13748. Demoro, B.; Caruso, F.; Rossi, M.; Benitez, D.; Gonzalez, M.; Cerecetto, H.; Galizzi, M.; Malayil, L.; Docampo, R.; Faccio, R.; Mombru, A. W.; Gambino, D.; Otero, L. Dalton Trans. 2012, 41, 6468-6476. Man, S. P.; Motevalli, M.; Gardiner, S.; Sullivan, A.; Wilson, J. Polyhedron 2006, 25, 1017-1032. Saad, A.; Rousseau, G.; El Moll, H.; Oms, O.; Mialane, P.; Marrot, J.; Parent, L.; Mbomekalle, I. M.; Dessapt, R.; Dolbecq, A. J. Clust. Sci. 2014, 25, 795-809. Saad, A.; Zhu, W.; Rousseau, G.; Mialane, P.; Marrot, J.; Haouas, M.; Taulelle, F.; Dessapt, R.; Serier-Brault, H.; Riviere, E.; Kubo, T.; Oldfield, E.; Dolbecq, A. Chem.: A Eur. J. 2015, 21, 10537-10547. Sikorska, M.; Gazdab, M.; Chojnackia, J. Acta Crystallogr. Sect. E: Struct. Report. Online 2012, 68, m820-m821. Tan, H. Q.; Chen, W. L.; Liu, D.; Feng, X. J.; Li, Y. G.; Yan, A. X.; Wang, E. B. Dalton Trans. 2011, 40, 8414-8418. Tan, H. Q.; Chen, W. L.; Liu, D.; Li, Y. G.; Wang, E. B. Dalton Trans. 2010, 39, 12451249. Coiro, V. M.; Lamba, D. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1989, 45, 446448. Deacon, G. B.; Greenhill, N. B.; Junk, P. C.; Wiecko, M. J. Coord. Chem. 2011, 64, 179185. Fernandez, D.; Vega, D.; Ellena, J. A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2003, 59, O289-O292. Fernandez, D.; Vega, D.; Goeta, A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2003, 59, M543-M545. Fernandez, D.; Vega, D.; Goeta, A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2002, 58, M494-M497.


Page 30 of 35

Page 31 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(23) Gossman, W. L.; Wilson, S. R.; Oldfield, E. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2002, 58, M599-M600. (24) Gossman, W. L.; Wilson, S. R.; Oldfield, E. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2003, 59, M33-M36. (25) Malpezzi, L.; Maccaroni, E.; Carcano, G.; Ventimiglia, G. J. Therm. Anal. Calorim. 2012, 109, 373-379. (26) Vachal, P.; Hale, J. J.; Lu, Z.; Streckfuss, E. C.; Mills, S. G.; MacCoss, M.; Yin, D. H.; Algayer, K.; Manser, K.; Kesisoglou, F.; Ghosh, S.; Alani, L. L. J. Med. Chem. 2006, 49, 3060-3063. (27) Van Brussel, E. M.; Gossman, W. L.; Wilson, S. R.; Oldfield, E. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2003, 59, O93-O94. (28) Vega, D.; Baggio, R.; Piro, O. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1998, 54, 324-327. (29) Vega, D.; Fernendez, D.; Ellena, J. A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2002, 58, M77-M80. (30) Zhang, Y. H.; Hudock, M. P.; Krysiak, K.; Cao, R.; Bergan, K.; Yin, F. L.; Leon, A.; Oldfield, E. J. Med. Chem. 2007, 50, 6067-6079. (31) Demadis, K. D.; Panera, A.; Anagnostou, Z.; Varouhas, D.; Kirillov, A. M.; Cisarova, I. Cryst. Growth Des. 2013, 13, 4480-4489. (32) El Moll, H.; Kemmegne-Mbouguen, J. C.; Haouas, M.; Taulelle, F.; Marrot, J.; Cadot, E.; Mialane, P.; Floquet, S.; Dolbecq, A. Dalton Trans. 2012, 41, 9955-9963. (33) El Moll, H.; Zhu, W.; Oldfield, E.; Rodriguez-Albelo, L. M.; Mialane, P.; Marrot, J.; Vila, N.; Mbomekalle, I. M.; Riviere, E.; Duboc, C.; Dolbecq, A. Inorg. Chem. 2012, 51, 79217931. (34) Fernandez, D.; Polla, G.; Vega, D.; Ellena, J. A. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, 60, M73-M75. (35) Gossman, W. L.; Wilson, S. R.; Oldfield, E. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2003, 59, M33-M36. (36) Guenin, E.; Monteil, M.; Bouchemal, N.; Prange, T.; Lecouvey, M. Eur. J. Org. Chem. 2007, 20, 3380-3391. (37) Ruscica, R.; Bianchi, M.; Quintero, M.; Martinez, A.; Vega, D. R. J. Pharm. Sci. 2010, 99, 4962-4972. (38) Su, Y. H.; Cao, D. K.; Duan, Y.; Li, Y. Z.; Zheng, L. M. J. Solid State Chem. 2010, 183, 1588-1594. (39) Sato, M.; Grasser W.; Endo, N.; Akins, R.; Simmons, H.; Thompson, D. D.; Golub, E.; Rodan, G.A. J. Clin. Invest. 1991, 88, 2095–2105. (40) Epstein, S. Drug Aging. 2006, 23, 617-625. (41) Shinkai, I.; Ohta, Y. Org.-Biol. Med. Chem. 1996, 4, 3-4. (42) Cipla K. Finished Product Specification. Test and methods. Alendronate sodium trihydrate, 1999. (43) The Merck Index. An Encyclopedia of Chemicals, Drugs and Biologicals; 15ª ed., p. Merck e Co. Inc. 2013. (44) Merck & Co. Alendronate prescribing information. West Point. Pennsylvania, USA, Sept 1995. (45) Meloun, M.; Ferencíkova, Z.; Netolicka, L.; Pekarek T. J. Chem. Eng. Data. 2011, 56, 3848–3854. ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(46) Boichenko, A. P.; Markov, V. V.; Kong, H. L.; Matveeva, A. G.; Loginova, L. P. Cent. Eur. J. Chem. 2009, 7, 8–13. (47) Hagele, G.; Szakacs, Z.; Ollig, J.; Hermens, S.; Pfaff, C. Heteroatom Chem. 2000, 11, 562-582. (48) Kabachnik, M. N.; Medved, T. Y.; Dyatlova, N .M.; Polikarpov, Y. M.; Shcherbakov, B. K.; Belskiy, F.K. Izv. Akad. Nauk USSR, Ser. Khim 1978, 433. (49) Dyba, M.; Jezowska-Bojczuk, M.; Kiss, E.; Kiss, T.; Kozlowski, H.; Leroux, Y.; El Manouni, D. J. Chem. Soc., Dalton Trans. 1996, 1119–1123. (50) Nancollas, G. H.; Tang, R.; Phipps, R. J.; Henneman, Z.; Gulde, S.; Wu, W.; Mangood, A.; Russell, R. G.; Ebetino, F. H. Bone 2006, 38, 617–627. (51) Hounslow, A. M.; Carran, J.; Brown, R. J.; Rejman, D.; Blackburn, G. M.; Watts, D. J. J. Med. Chem. 2008, 51, 4170–4178. (52) Cong, H. L.; Boichenko, A. P.; Levin, I. V.; Matveeva, A. G.; Loginova, L. P. J. Mol. Liq. 2010, 154, 76–81. (53) Boichenko, A. P.; Sidorenko, A.Yu.; Markov, V. V.; Cong, H. L.; Matveeva, A. G.; Loginova, L. P. Kharkov Univ. Bull. 2010, 895, 56–64. (54) Finkelstein, N.; Lidor-hadas, R.; Aronhime, J. TEVA Pharmaceutical Industries, Ltd., Tigva (IL) 2001, 09, 756-898. (55) Asnani, M.; Vyas, K.; Bhattacharya, A.; Devarakonda, S.; Chakraborty, S.; Mukherjee, A. K. J. Pharm. Sci. 2009, 98, 2113−2121. (56) Vega, D.; Baggio, R.; Garland, M. T. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1996, 52, 2198−2201. (57) Deacon, G. B.; Forsyth, C. M.; Greenhill, N. B.; Junk, P. C.; Wang, J. Cryst. Growth Des. 2015, 15, 4646−4662. (58) Kieczykowski, G. R.; Melillo, D. G.; Jobson, R. B. Merck Co., Inc., Rahway, U.S. Patent, Patent number: 4, 922, 007, 1990 (59) Sienkiewicz, B.; Kowalski, P.; Ossowska, K.; Potok, J.; Cizmek, -C.; Horvat, M.; Tudja, P.; Danilovski, A. U.S. Patent, US 2005/0113343A1, 2005. (60) United States Pharmacopeia National Formulary—USP38 NF33; U.S. Pharmacopeial Convention: Rockville, MD, USA, 2015. (61) Leroux, Y.; El Manouni, D.; Safsaf, A.; Neuman, A.; Giller, H. Phosphorous, Sulfur Silicon Relat. Elem. 1991, 63, 181–191. (62) Ohanessian, J.; Avenel, D.; El Manouni, D.; Benramdane, M. Phosphorus, Sulfur Silicon Relat. Elem. 1997,129, 99–110. (63) Alvarez, E.; Marquez, A. G.; Devic, T.; Steunou, N.; Serre, C.; Bonhomme, C.; Gervais, C.; Izquierdo-Barba, I.; Vallet-Regi, M.; Laurencin, D.; Mauri, F.; Horcajada, P. CrystEngComm 2013, 15, 9899-9905. (64) Roldán, E. J. A.; Quattrocchi, O.; Zanetti, D.; Piccinni, E.; Tessler, J.; Caballero, L. E.; Lloret, A. P. Arzneim.-Forsch./Drug Res. 2005, 55, 93-101. (65) De Groen, P. C.; Lubbe, D. F.; Hirsch, L. J.; Daifotis, A.; Stephenson, W.; Freedholm, D.; Pryor-Tillotson, S.; Seleznick, M. J.; Pinkas, H.; Wang, K. K. N. Engl. J. Med. 1996, 355, 1016 –1021. (66) Ryan, J. M.; Kelsey, P.; Ryan, B. M.; Mueller, P. R. Radiology 1998, 206, 389-391. (67) Lamprecht, G. J. Pharm. Sci. 2009, 98, 3575–3581. (68) Mahmood, A.; Khan, I. U.; Longo, R. L.; Irfan, A.; Shahzad, S. A. C. R. Chimie 2015, 18, 422–429. ACS Paragon Plus Environment

Page 32 of 35

Page 33 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(69) Llinàs, A.; Goodman, J.M. Drug Discov. 2008, 13, 198-210. (70) Bonfilio, R.; Leal, J. S.; Santos, O. M. M.; Pereira, G. R.; Doriguetto, A. C.; de Araujo, M. B. J. Pharm. Biomed. Anal. 2014, 88, 562-570. (71) Bonfilio, R.; Pires, S. A.; Ferreira, L. M. B.; de Almeida, A. E.; Doriguetto, A. C.; de Araujo, M. B.; Salgado, H. R. N. J. Pharm. Sci. 2012, 101, 794-804. (72) Ellena, J.; Bocelli, M. D.; Honorato, S. B.; Ayala, A. P.; Doriguetto, A. C.; Martins, F. T. Cryst. Growth Des. 2012, 12, 5138-5147. (73) Legendre, A. O.; Silva, L. R. R.; Silva, D. M.; Rosa, I. M. L.; Azarias, L. C.; de Abreu, P. J.; de Araujo, M. B.; Neves, P. P.; Torres, C.; Martins, F. T.; Doriguetto, A. C. CrystEngComm 2012, 14, 2532-2540. (74) Santos, O. M. M.; Dias Reis, M. E.; Jacon, J. T.; de Sousa Lino, M. E.; Simoes, J. S.; Doriguetto, A. C. Braz. J. Pharm. Sci. 2014, 50, 1-24. (75) Martins, F. T.; Bocelli, M. D.; Bonfilio, R.; de Araujo, M. B.; de Lima, P. V.; Neves, P. P.; Veloso, M. P.; Ellena, J.; Doriguetto, A. C. Cryst. Growth Des. 2009, 9, 3235-3244. (76) Martins, F. T.; Bonfilio, R.; Rosa, I. M. L.; Santos, L. M.; Santos, O. M. M.; Araujo, M. B.; Doriguetto, A. C. CrystEngComm 2013, 15, 3767-3771. (77) Martins, F. T.; de Abreu, P. J.; Azarias, L. C.; Villis, P. C. M.; de Campos Melo, A. C.; Ellena, J.; Doriguetto, A. C. CrystEngComm 2012, 14, 6173-6177. (78) Martins, F. T.; de Lima, P. V.; Azarias, L. C.; de Abreu, P. J.; Neves, P. P.; Legendre, A. O.; de Andrade, F. M.; de Oliveira, G. R.; Ellena, J.; Doriguetto, A. C. CrystEngComm 2011, 13, 5737-5743. (79) Martins, F. T.; Doriguetto, A. C.; Ellena, J. Cryst. Growth Des. 2010, 10, 676-684. (80) Martins, F. T.; Legendre, A. O.; Honorato, S. B.; Ayala, A. P.; Doriguetto, A. C.; Ellena, J. Cryst. Growth Des. 2010, 10, 1885-1891. (81) Martins, F. T.; Paparidis, N.; Doriguetto, A. C.; Ellena, J. Cryst. Growth Des. 2009, 9, 5283-5292. (82) Santos, L. M.; Santos, O. M. M.; Mendes, P. F.; Landre Rosa, I. M.; da Silva, C. C.; Bonfilio, R.; de Araujo, M. B.; Boralli, V. B.; Doriguetto, A. C.; Martins, F. T. J. Pharm. Biomed. Anal. 2016, 118, 101-104. (83) Santos, O. M. M.; Jacon Freitas, J. T.; Laignier Cazedey, E. C.; de Araujo, M. B.; Doriguetto, A. C. Molecules 2016, 21. (84) Santos, O. M. M.; Silva, D. M.; Martins, F. T.; Legendre, A. O.; Azarias, L. C.; Rosa, I. M. L.; Neves, P. P.; de Araujo, M. B.; Doriguetto, A. C. Cryst. Growth Des. 2014, 14, 37113726. (85) Kuljanin, J.; Jankovic, I.; Nedeljkovic, J.; Prstojevic, D.; Marinkovic, V. J. Pharm. Biomed. Anal. 2002, 28, 1215-1220. (86) Lovdahl, M. J.; Pietrzyk, D. J. J. Chromatogr. A 1999, 850, 143-152. (87) Qin, X. Z.; Tsai, E. W.; Sakuma, T.; Ip, D. P. J. Chromatogr. A 1994, 686, 205-212. (88) Tsai, E. W.; Chamberlin, S. D.; Forsyth, R. J.; Bell, C.; Ip, D. P.; Brooks, M. A. J. Pharm. Biomed. Anal. 1994, 12, 983-991. (89) Tsai, E. W.; Ip, D. P.; Brooks, M. A. J. Chromatogr. 1992, 596, 217-224. (90) Tsai, E. W.; Singh, M. M.; Lu, H. H.; Ip, D. P.; Brooks, M. A. J. Chromatogr. 1992, 626, 245-250. (91) Zacharis, C. K.; Tzanavaras, P. D. J. Pharm. Biomed. Anal. 2008, 48, 483-496.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(92) Hage, D. S.; James, D. C. Química analítica e análise quantitativa, tradução Midori Yamamoto; revisão técnica Edison Wendler. 1. ed. São Paulo: Pearson Prentice Hall, p. 460, 2012. (93) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; Van de Streek, J.; Wood, P. A. Mercury CSD 2.0 J. Appl. Crystallogr. 2008, 41, 466–470. (94) Brasil. Ministério da Saúde. Resolução RE nº 899, de 29 de maio de 2003. Determina a publicação do "Guia para validação de métodos analíticos e bioanalíticos”. Diário Oficial da União, Brasília, 02 de jun. 2003. Available on line: http://redsang.ial.sp.gov.br/site/docs_leis/vm/vm1.pdf (accessed on 07/01/2016). (95) International Conference on Harmonization. Guidance for Industrty: Q2B- Validation of Analytical Procedures: Methodology. U.S. Department of Health and Human Services, Food and Drug Administration,Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), November of 1996. Available on line: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances /ucm073384.pdf (accessed on 07/01/2016). (96) Brasil. Ministério da Saúde. Nota técnica nº 003/2013, 2013. Available on line: 2003. http://portal.anvisa.gov.br/web/coopi/perguntas-e-respostas-sobre-a-previa-anuencia-daanvisa; http://portal.anvisa.gov.br/documents/33836/349757/Nota+t%C3%A9cnica+n%C2%BA+0 3+de+2013+-+CEFAR-GTFAR-GGMED-Anvisa/2c769030-a303-4c8f-adc85fd781695725 (accessed on 24/08/2016). (97) Brasil. Ministério da Saúde. RDC nº 31 de agosto de 2010, 2010. Available on line: http://www.labfar.com.br/labfar-cebio/legislacao/RDC_31_2010.pdf (accessed on 07/01/2016). (98) Allen, F.H. Acta Crystallogr. B: Struct. Sci. 2002, 58, 380–388. (99) OLEX2, software from Durham University, DH1 3LE , UK. OlexSys Ltd, 2016. (100) Nesterenko, V.F.; Bondar, M.P.; Ershov, V. Conference Proceedings, Colorado Springs, CO, USA 1994, 309, 1173–1176. (101) Borgadus, J. B.; Blackwood, R. B., Jr. J. Pharm. Sci. 1979, 68, 188. For Table of Contents Use Only

Solid-state Phase Transition Mechanism and Physical–Chemical Study of the Crystal Forms of Monosodium Alendronate: Trihydrate versus Anhydrate Edeilson V. Gonzaga,†,§ André L. M. Viana,‡ Olimpia M. M. S. Viana,†,§ Antonio C. Doriguetto*,§


Page 34 of 35

Page 35 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


†

Núcleo Controle Qualidade de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil ‡ Laboratório Central de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil § Laboratório de Cristalografia, Instituto de Química, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil

Synopsis A solid-state reversible dehydration/rehydration mechanism involving monosodium alendronate, which is an Active Pharmaceutical Ingredient used for bone disorders, is given for the first time. Using an alternative method of quantification, the two crystal forms are shown to have different solubilities and dissolution rates.


Solid-State Phase Transition Mechanism and ... - ACS Publications

Recommend Documents