Amino Acids as Co-amorphous Excipients for Simvastatin and

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Amino acids as co-amorphous excipients for simvastatin and glibenclamide: physical properties and stability Riikka Laitinen, Korbinian Loebmann, Holger Grohganz, Clare Strachan, and Thomas Rades Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp500107s • Publication Date (Web): 22 May 2014 Downloaded from http://pubs.acs.org on May 27, 2014

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Molecular Pharmaceutics

Amino acids as co-amorphous excipients for simvastatin and glibenclamide: physical properties and stability Riikka Laitinena,*, Korbinian Löbmannb, Holger Grohganzb, Clare Strachanc, Thomas Radesb a

School of Pharmacy, University of Eastern Finland, Kuopio, Finland

b

c

Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark

Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Finland

*Corresponding author

ACS Paragon Plus Environment

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ABSTRACT GRAPHIC


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ABSTRACT: Co-amorphous drug mixtures with low molecular weight excipients have recently been shown to be a promising approach for stabilization of amorphous drugs and thus an alternative to the traditional amorphous solid dispersion approach using polymers. However, the previous studies are limited to a few drugs and amino acids. To facilitate the rational selection of amino acids, the practical importance of the amino acid coming from the biological target site of the drug (and associated intermolecular interactions) needs to be established. In the present study, the formation of co-amorphous systems using cryomilling and combinations of two poorly water-soluble drugs (simvastatin and glibenclamide) with the amino acids aspartic acid, lysine, serine and threonine was investigated. Solid-state characterization with x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) revealed that the 1:1 molar combinations simvastatin-lysine, glibenclamide-serine and glibenclamide-threonine and the 1:1:1 molar combination glibenclamide-serine-threonine formed co-amorphous mixtures. These were homogeneous, single phase blends with weak intermolecular interactions in the mixtures. Interestingly, a favorable effect by the excipients on the tautomerism of amorphous glibenclamide in the co-amorphous blends was seen, as the formation of the thermodynamically less stable imidic acid tautomer of glibenclamide was suppressed compared to the pure amorphous drug. Furthermore, the co-amorphous mixtures provided a physical stability advantage over the amorphous drugs alone.

KEYWORDS: amorphous, co-amorphous, amino acid, stability, tautomerism


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Introduction

Currently, approximately 40% of drugs on the market and 75% of those in discovery pipelines exhibit poor aqueous solubility1. Several methods can be employed to increase the apparent solubility and thus potentially the bioavailability of these problematic drugs, from which nanocrystalline and amorphous formulations appear to be the most common2-5. However, the thermodynamic instability of amorphous materials makes them prone to recrystallization, which can happen during manufacturing, storage or dissolution (administration)6-10, 9. A common strategy to improve the stability of amorphous drugs is the formation of glass solutions of a drug with polymers where the drug is molecularly dispersed within the polymer1, 6, 10. These systems can provide stabilization through an increased glass transition temperature (Tg) of the system and molecular interactions between the drug and the polymer11. However, problems in long-term stability can still occur, largely due to the hygroscopicity of the polymers used. In addition, limited miscibility of the drug in a polymer11-13 and difficulties with manufacturing and processing of solid dispersions into final dosage forms14 have limited the applicability of this approach. So far, only a few products of this type have reached the market.

In order to overcome these problems, alternative stabilization approaches, where the polymer has been replaced by a low molecular weight excipient, have recently been introduced 15-18. For example, in these so-called co-amorphous systems a pharmacologically relevant combination of two drugs has been used to produce highly stable and fast dissolving mixtures. It has been discovered that enhanced dissolution and stability can be mainly attributed to solid-state molecular interactions between the two molecules 15, 18, 19. Furthermore, promising candidates for


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combination therapy can be provided by this approach15, 18. However, the feasibility of such coamorphous systems for practical applications (i.e. dosage forms) is somewhat limited by the requirement of suitable, pharmacologically relevant drug pairs. Therefore, this promising concept was further developed into combinations of a drug and a pharmacologically inactive molecule, such as amino acids (AAs)20. In a recent study, the AAs were chosen based on the knowledge about the specific AAs interacting with the drug in the binding sites of a biological receptor. It was hypothesized that such AAs would interact strongly with the drug molecule upon preparation of a co-amorphous mixture in the solid state, providing a stabilizing effect on the amorphous material. For the drugs carbamazepine (CBZ) and indomethacin (IND) and the AAs arginine (ARG), phenylalanine (PHE), tryptophan (TRP) and tyrosine (TYR), it was observed that vibrational ball milling resulted in several co-amorphous blends at the molar ratios 1:1 and 1:1:120, 21. The authors found that CBZ could only be transferred into the amorphous form in combination with its receptor amino acid TRP, whereas IND could be prepared in its amorphous and/or co-amorphous form in several combinations. TRP was found to have a good co-amorphization potential with the drugs (regardless of being in the corresponding drug receptor). However, specific interactions were only found in the co-amorphous mixtures that contained at least one amino acid from the biological target site of the drug21. The co-amorphous mixtures showed excellent physical stability which was attributed to elevated Tgs of the mixtures compared to the individual drugs, molecular level mixing and drug-AA molecular interactions. While the studies on these two drugs have shown the potential of this method for amorphous form stabilisation, other drug and amino acid combinations need to be investigated to better establish the general feasibility of this approach. In addition, to help rationalize amino acid selection it is important to gain insight into


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the drug-AA interactions occurring in these systems. In this way, the practical importance of the AA coming from the biological target site of the drug that it is combined with can be established. In the current study, the two Biopharmaceutics Classification System (BCS) class II drugs simvastatin (SVS) and glibenclamide (GBC) were combined with their receptor AAs (Table 1)22, 23

. For SVS, these were the amino acids aspartic acid (ASP), lysine (LYS) and serine (SER),

while SER was selected for GBC. As a negative control with respect to receptor dependent molecular interactions, the highly water soluble AA threonine (THR) was used as a non-receptor AA for both of the drugs. The drug-AA mixtures were cryomilled at the molar ratios 1:1 or 1:1:1. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fouriertransform infrared spectroscopy (FTIR) were used for solid-state characterization. Physical stability of the amorphous formulations was investigated at elevated humidity and temperature.

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Experimental Section

2.1 Materials Simvastatin (SVS, 418.6 g/mol, USP grade), glibenclamide (GBC, 494.0 g/mol, USP grade), L-aspartic acid (ASP, 133.1 g/mol, medicine grade), L-lysine (LYS, 146.2 g/mol, medicine grade), L-serine (SER, 105.1 g/mol, medicine grade) and L-threonine (THR, 119.1 g/mol, medicine grade) were all purchased from Hangzhou Dayangchem CO Ltd (Hangzhou City, China). All compounds were used as received. ASP, LYS and SER are receptor AAs for SVS and SER is a receptor AA for GBC (Table 1). There are also other receptor AAs found in the literature (GLU (glutamine), LEU (leucine), VAL (valine) and ALA (alanine) for SVS24 and


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PRO (proline) for GBC25), but only AAs with acyclic side chains allowing hydrogen bonding were included in this study. The chemical structures of the materials are shown in Figure 1. The polymorphic forms were identified using XRPD and the Cambridge Structural Database reference codes as: EJEQAL for simvastatin, DUNXAL for glibenclamide, LASPRT for Laspartic acid, LSERIN01 for L-serine, LTHREO for L-threonine. There were no crystal structures of L-lysine in the database, but its experimental x-ray powder diffractogram revealed it was crystalline with the strongest diffraction peaks at 10.2, 18.4, 19.5, 20.5 and 25.5 °2θ.

Table 1. The receptor binding-properties of the amino acid selected for the study. Amino acid

Binding properties

Reference

L-aspartic acid (ASP)

Binds to simvastatin in 3-hyrdroxy-3-methyglutaryl coenzyme 22 A (HMG-CoA) binding site

L-lysine (LYS)

Binds to simvastatin in HMG-CoA binding site

22

L-serine (SER)

Binds to simvastatin in HMG-CoA binding site

22

Binds to glibenclamide in ATP-sensitive potassium channel 23 (KATP) channel binding site L-threonine (THR)

Non-receptor amino acid for both of the drugs


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Figure 1. Chemical structures of the drugs simvastatin (SVS) and glibenclamide (GBC) and the amino acids aspartic acid (ASP), lysine (LYS), serine (SER) and threonine (THR).

2.2 Methods 2.2.1 Preparation of the amorphous materials Co-amorphous blends were prepared by cryomilling (CM) at 30 Hz for 60 min in an oscillatory ball mill (Mixer Mill MM400, Retch GmbH & Co., Haan, Germany). A total mass of 500 mg of the crystalline compounds, or the appropriate amount of drug and amino acid(s) at the molar ratios 1:1 (drug:AA) or 1:1:1 (drug:AA1:AA2), respectively, was placed into 25 ml milling jars with two 15 mm stainless steel balls. The milling jars were immersed in liquid nitrogen for 2 minutes prior to and during milling (at 10 minutes intervals). After milling, the chambers were allowed to reach the environmental temperature in a desiccator before opening in


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order to prevent moisture absorption. Subsequently the samples were retrieved from the chambers, immediately transferred to 4°C/0% humidity and stored there until analysis.

2.2.2 X-ray powder diffraction (XRPD) XRPD measurements were performed with a Bruker D8 DISCOVER system (Bruker AXS GmbH, Germany) using Cu Kα radiation with λ = 1.542 Å and a divergence slit of 1°. The samples were scanned at 40 kV and 40 mA from 5 to 35° 2θ using a scanning speed of 0.1285°/min and a step size of 0.0084°.

2.2.3 Differential scanning calorimetry (DSC) DSC thermograms were obtained using a Mettler Toledo DSC823e (Mettler Toledo, Schwerzenbach, Switzerland) equipped with an intercooler (Mettler Toledo, METT-FT900 Julabo, Switzerland) and an autosampler (TS080IRO Sample Robot, Mettler Toledo, Schwerzenbach, Switzerland) under a nitrogen flow of 50 ml/min. Calibration of temperature and heat flow was conducted with indium, lead, zinc, and highly purified water standards. Sample powders (approx. 10 mg) were weighed with a microbalance (Sartorius SE2, Sartorius AG, Germany) and analyzed in sealed 40 µl aluminum pans (Mettler Toledo, Switzerland) with a pierced lid. Each measurement was performed in triplicate. The samples were heated at a heating rate of 10°C/min starting from -50°C. CM samples of SVS and GBC were heated up to 150°C and 190°C, respectively. Samples containing AAs were


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heated up to 280°C (ASP), 235°C (LYS), 240°C (SER) and 270°C (THR). The glass transition temperatures (Tg, midpoint) and melting points (Tm, onset) were determined using a STARe software (Mettler Toledo, Switzerland). To predict the Tg-values of the mixtures the Gordon-Taylor (GT) equation and the SimhaBoyer rule were used26. This was however, only possible for the SVS-LYS combinations, since a Tg could be obtained only for LYS from the literature27. The Tg of SVS measured by melt quenching in the DSC, and densities of 1.11 g/cm-3 and 1.237 g/cm-3 for SVS and LYS, respectively, were used28, 29.

2.2.4 Fourier-transform infrared spectroscopy (FTIR) A Nicolet Nexus 870 FTIR spectrometer with a liquid nitrogen cooled MCT (mercuric cadmium telluride) B detector (Thermo Electron Corp, Madison, WI, USA), equipped with an attenuated total reflectance (ATR) accessory (Smart Endurance, Single-reflection ATR diamond composite crystal) was used for obtaining the IR spectra. Spectra were collected over a range of 4000-500 cm-1 (64 scans, resolution 4 cm-1).

2.2.6 Stability studies The amorphous samples were stored in desiccators under the following conditions: 4°C/0% relative humidity (RH), ambient temperature (approx. 22°C)/60% RH and 40°C/0% RH. RH of 0% was achieved with phosphorous pentoxide and RH of 60% with a saturated NaBr solution.


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The samples were analyzed regularly (weekly for the first month, then every two weeks until 3 months, thereafter monthly) with XRPD and FTIR until onset of recrystallization was observed. The onset of recrystallization was reflected by the appearance of recrystallization peaks arising from the amorphous halo in the XRPD diffractograms.

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Results and discussion

In order to evaluate the feasibility of the co-amorphous amino acids approach, the different drug-AA mixtures were investigated on their success of turning into a co-amorphous system, their physical stability and the underlying mechanism for an increased stability.

3.1. X-ray powder diffraction (XRPD) XRPD measurements of the freshly cryomilled samples are shown in Figures 2a-c. The pure drugs were X-ray amorphous after a milling time of 60 min. In contrast, it was not possible to transform the AAs into their amorphous forms by cryomilling, as indicated by the remaining reflections of the respective crystalline forms in Figure 2a. There was also no evidence of different crystal forms being created in any of the samples. However, when the AAs were cryomilled with the drugs the results were different. In the case of SVS (Figure 2b), it was observed that even though the AAs ASP, LYS, and SER were all receptor AAs for SVS22, only LYS was able to form a co-amorphous mixture with the drug with the preparation method and conditions used. In addition, the non-receptor AA THR did not form


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an amorphous mixture with SVS alone or in combination with LYS (1:1:1 molar ratio). In SVSLYS-THR CM, the degree of crystallinity was significantly reduced and the remaining crystalline reflections were found to originate from THR (Figure 2b, Table 2). With GBC (Figure 2c), a binary combination with its receptor amino acid SER23 resulted in an X-ray amorphous mixture. In contrast to SVS, GBC also formed a binary co-amorphous mixture with the nonreceptor AA THR and in ternary combination with SER and THR. Combinations with nonreceptor AAs ASP and LYS resulted in mixtures with residual, although significantly reduced, crystallinity (with the same polymorphs, Table 2). Polarized light microscopy (PLM) analysis (Figure 1 in Supporting Information) confirmed the amorphousness of SVS CM, SVS-LYS CM, GBC CM, GBC-SER CM, GBC-THR CM and GBC-SER-THR CM. Only these fully amorphous combinations were characterized further. An overview of the success of amorphisation and remaining crystalline components is given in Table 2.

a)


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b)

c)

Figure 2. XRPD diffractograms of a) cryomilled pure substances; b) cryomilled SVS mixtures with the amino acids ASP, LYS, SER and THR and c) cryomilled GBC mixtures with the amino acids ASP, LYS, SER and THR.


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Table 2. Melting temperatures (Tm) of the crystalline starting materials and the possible amorphization by cryomilling of the pure drugs and the drug mixtures with amino acids at molar ratios of 1:1 and 1:1:1, recrystallization (Trc) temperatures and the glass transition (Tg) temperatures for the fully amorphous samples. Remaining crystalline component in mixture

Trc [°°C]

Tg [°°C]

139.9±0.2

ND.

ND.

32.5±0.6 a

GBC

174.2±0.2

ND.

ND.

ND.b

SVS CM

131.18±1.4

Yes

ND.

70.5±1.2

29.0±0.6

GBC CM

167.0±0.6

Yes

ND.

127.1±0.3

71.9±0.7

ASP

226.9±4.1

No

NA

NA

ND.

LYS

212.4±0.5

No

NA

NA

ND.

SER

217.3±1.0

No

NA

NA

ND.

THR

252.1±1.0

No

NA

NA

ND.

SVS-ASP 1:1

NA

No

ASP

NA

NA

SVS-LYS 1:1

134.1±0.1 (SVS) 199.9±3.2 (LYS)

Yes

ND.

107.0±1.2

33.2±0.9

SVS-SER 1:1

NA

No

SER

NA

NA

SVS-THR 1:1

NA

No

THR

NA

NA

SVS-LYS-THR 1:1:1

NA

No

THR

NA

NA

GBC-ASP 1:1

NA

No

ASP

NA

NA

GBC-LYS 1:1

NA

No

LYS

NA

NA

Material

Tm [°°C]

SVS

Amorphization by CM


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GBC-SER 1:1

186.9±2.6

Yes

ND.

113.8±1.4

70.1±1.3

GBC-THR 1:1

193.4±0.7

Yes

ND.

108.1±0.3

58.4±0.6

GBC-SER-THR 1:1:1

180.2±3.8

Yes

ND.

116.2±1.0

62.5±4.5

SER-THR 1:1

NA

No

SER, THR

NA

a

For melt-quenched SVS The Tg for melt-quenched GBC cannot be measured due to thermal degradation40 ND= not detected NA= not analyzed (or not applicable) b


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The results of the current and previous studies with drug-AA systems20 show that coamorphization is possible also with AAs that are not from the biological target site of the drug.

3.2 Differential scanning calorimetry (DSC) For all the amorphous samples, a Tg and a recrystallization event above the Tg was observed (Table 2, thermograms in Figure 2a and b in Supporting Information). The Tg values (Table 2) obtained for individually cryomilled drugs agreed well with previously published results18, 30. All co-amorphous mixtures had a single Tg in the DSC thermograms which indicated the formation of single-phase co-amorphous mixtures31, 32 . Compared to the Tg values of the amorphous drugs, the co-amorphous mixture SVS-LYS had a Tg slightly higher than SVS CM, GBC-SER had a Tg similar to GBC CM, and GBC-THR had a Tg clearly lower than GBC CM. This indicates that amorphous THR may have a low Tg and acts as a plasticizer in the mixture, which could be detrimental for stability. In the case of the ternary mixture GBC-SER-THR, the Tg-value was lower than that of GBC CM and GBC-SER CM but higher than in the binary mixture with GBCTHR. Unfortunately, it was not possible to form an amorphous mixture of SER-THR by cryomilling, thus no Tg-value for this combination was obtained. Furthermore, cryomilling was not able to convert the AAs into amorphous forms (Figure 2a) and quench-cooling resulted in thermal degradation of the AAs. In general, amorphization of AAs has been found to be difficult and only a few AA Tgs are available in the literature. The only available Tg in the context of this study was that of LYS (68°C)27. Using this value, the theoretical Tg for SVS-LYS CM was


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calculated (by the Gordon-Taylor equation) to be 40.3°C which was higher than the experimentally observed Tg (33.2°C, Table 2). Generally this is indicative of weaker intermolecular bonding in the blend compared to the individual amorphous components33-36 or of an increase in free volume due to mixing37. A positive deviation from the theoretical Tg would suggest that the amount and strength of bonding between the components in the mixture could be somewhat stronger than interactions existing in the individual components15, 34. 1:1 intermolecular interactions have been found to be responsible for increased stability instead of increased Tg in co-amorphous mixtures. A co-amorphous mixture with the highest Tg is not always the most stable one, instead the 1:1 mixtures often have the most positive deviation from the ideal /theoretical) behavior due to 1:1 molecular interactions between the molecules which leads to superior stability over other mixture ratios15, 16,38. In the first study to introduce the concept of forming drug-AA co-amorphous mixtures, the drugs IND and CBZ were combined with receptor and non-receptor amino acids, the Tg values of the co-amorphous mixtures formed were all found to be higher than those of the respective individual drugs20. Positive deviations from the theoretical Tg, predicted by the Gordon-Taylor equation, were observed for IND-ARG and IND-ARG-PHE which was found to be attributable to salt formation between IND and ARG 21

. No such positive deviation, indicating stabilizing SVS-LYS interaction, was found in this

study. Although LYS was found to increase the Tg of SVS-LYS CM compared to SVS CM the increase was less than predicted by the GT equation. The Tg of amorphous GBC itself was quite high (approx. 72°C) and based on the Tgs of the GBC-AA mixtures, Tg-values of the AAs SER and THR, acting as plastisizers in the mixtures are likely to be approx. 60°C or lower, especially with THR.


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The recrystallization onset temperatures (Trc) can be considered as indicative of physical stability of an amorphous system36. Trc for the cryomilled SVS and GBC were approximately 71°C and 127°C, respectively (Trc was not observed with quench cooled drugs, Table 2). In coamorphous mixtures, these were altered. In SVS-LYS CM, the Trc increased to 107°C, pointing towards a stabilizing effect with formation of the co-amorphous mixture with LYS. This is contradictory to the negative deviation from the theoretical Tg found for SVS-LYS CM. Furthermore, two melting endotherms, with reduced onset temperatures compared to those for pure crystalline SVS and LYS, were observed after Trc. This indicates that both SVS and LYS recrystallized (at least partly) at Trc and that there might be interactions between the components (Table 2, Supporting Information). The Trc values of the co-amorphous GBC formulations, were lower than those of GBC CM (Table 2). In these mixtures only one melting endotherm (higher than Tm of GBC) was observed, which might indicate that these AAs might have a stronger tendency towards crystallization37 than GBC and thus the first recrystallizing component would be the AA in the mixture instead of the drug. Thus, based on the DSC studies, conclusions on the interactions between GBC and the AAs cannot be drawn. However, the AAs decreased the Tg of the mixtures when compared to GBC CM. In contrast, with SVS-LYS CM stronger interactions are likely, as indicated by the increased Trc compared to SVS CM, even though a negative deviation from Gordon-Taylor behavior was observed.


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3.3. Fourier-transform infrared spectroscopy (FTIR) FTIR measurements were carried out to investigate molecular level interactions between the drugs and AA in the co-amorphous mixtures. As would be expected, all spectra of the cryomilled amorphous samples (Figure 3) contain less sharply defined peaks than those of their crystalline counterparts, which is due to the inherently higher degree of molecular disorder associated with the amorphous forms. Figure 3a and b show the effect of cryomilling on the crystalline drugs without amino acids present. The peak shifts observed for OH (from 3548 cm-1 to 3442 cm-1) and C=O (from 1695 to 1714 cm-1) moieties in SVS upon transformation into the amorphous form indicate changes in intermolecular hydrogen bonding and were consistent with previous results18. With GBC, the N-H stretching bands of the acylamino and carbamido groups (at 3369 cm-1 and 3313 cm-1 in the crystalline form, respectively) merged and shifted to 3377 cm-1 in the pure amorphous form. Furthermore, the carbonyl stretching bands (at 1714 cm-1 and 1616 cm-1 for the crystalline form) were especially broadened, with the latter carbonyl stretch of the carbamino group shifting to around 1626 cm-1. In addition, a shoulder appeared at 1655 cm-1, which can be attributed to C=N stretching on an imidic acid tautomer of GBC30, 41. These changes have previously been observed with amorphous GBC and suggest that the amide was converted predominantly into the imidic acid form upon amorphization41, 42. The imidic acid structure is a thermodynamically less stable tautomer compared to the amide form — stabilization by intramolecular hydrogen bonding between the imidic acid and the aryl ether oxygen has been suggested42, 43.


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In Figure 3c, the spectra for crystalline LYS, crystalline SVS-LYS PM and SVS-LYS CM are shown. As previously stated, amorphization of LYS was not possible and thus peak shifts can only be assigned with certainty for SVS in the co-amorphous blend when comparing with the spectrum of amorphous SVS. Several spectral features differed upon formation of co-amorphous SVS-LYS. In SVS-LYS CM, the OH peak of SVS (at 3552 cm-1 in PM and 3442 cm-1 in SVS CM) broadened to an even greater extent compared to SVS CM and appeared at approximately 3350 cm-1 (i.e. blue–shifted by 8 cm-1 compared to pure amorphous SVS). No other significant SVS peak shifts were observed in the SVS-LYS CM spectra which could be associated to other than mere amorphization of SVS. In the spectrum of crystalline LYS, the characteristic amide I and amide II bands were observed at 1572 cm-1 and 1509 cm-1 (Figure 3c)44, 45. These bands had merged to one large peak in co-amorphous SVS-LYS. Some shifts can also be observed for the aliphatic chain vibrations which have shifted from 1356 cm-1 and 1319 cm-1 in crystalline LYS to 1350 cm-1 and 1312 cm-1 in SVS-LYS CM. Without the amorphous LYS reference it is difficult to say whether these changes are due to only amorphization of LYS or to intermolecular interaction with SVS. Based on the minor changes in the vibrational modes of SVS, it is suggested that there is no clear evidence of strong intermolecular interactions between SVS and LYS in their co-amorphous mixture. The substaintailly less defined peaks of SVS in the coamorphous mixture compared to pure amorphous form are evidence of an even higher degree of disorder in the co-amorphous system than with the pure amorphous drug. A larger range of molecular arrangements is possible with two components mixing on the molecular level, and even more likely if specific and relatively strong intermolecular interactions do not predominate.


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In the case of GBC mixtures with the amino acids SER and THR, changes occurring in the NH stretching region (peaks at 3369 cm-1 and 3313 cm-1 in the crystalline form for SER and THR, respectively) and carbonyl stretching region (at 1714 cm-1 and 1616 cm-1 in the crystalline form for SER and THR, respectively) of acylamino and carbamido groups of GBC were somewhat similar compared to those observed with amorphization of GBC alone (Figures 3b, d-f). Interestingly, the shoulder that appeared at 1655 cm-1 upon amorphous conversion of GBC, indicating formation of an imidic acid, did not appear in any of the spectra of the co-amorphous mixtures. This suggests that formation of a co-amorphous mixture with SER and THR prevented the amide group of GBC from conversion to the thermodynamically less stable imidic acid form. For this to happen, interactions of some sort are likely to exist between GBC and the respective AA. This tautomerism has been reported in several studies for GBC alone and it has been observed to occur regardless of the preparation method30, 41, 42, 46. In contrast, to our knowledge, GBC tautomerism has not been investigated before in the presence of excipients and the results of our study suggest for the first time that formation of a binary co-amorphous mixture with an excipient (in this case SER, THR or both), prevented the amide group of GBC from conversion to the thermodynamically more unstable imidic acid form. However, the spectra of physical and co-amorphous mixtures were dominated by GBC vibrational modes, which made evaluation of the other changes occurring in the absorption bands assigned to the amino acids difficult. The GBC found at 1519 cm-1 in crystalline GBC, assigned to NH bending of the urea group47, had shifted to 1534 cm-1 in the spectrum of the co-amorphous mixture while the shift in amorphous GBC was to 1531 cm-1. . In the case of GBC-SER CM (Figure 3d), the SER carbonyl band (broad at 1584 cm-1 in crystalline SER), had shifted and merged to a peak at 1595 cm-1 (in the spectrum of crystalline GBC-SER PM this band was combined with the GBC band at 1591 cm-1


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which was somewhat broadened and red–shifted). This may indicate that this group is involved in an intermolecular interaction e.g. with the urea group of GBC but such a change primarily due to conversion to amorphous SER cannot be excluded. The same peak was much smaller in GBCTHR (Figure 3e), since THR has carbonyl absorption at 1622 cm-1. In the co-amorphous GBCTHR this peak has probably merged with the band at 1626 cm-1. The spectrum of co-amorphous ternary mixture GBC-SER-THR corresponds to the calculated average spectrum of coamorphous GBC-SER and GBC-THR (Figure 3f), and thus no evidence of new interactions formed in this mixture with respect to GBC-SER and GBC-THR could be found


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a)

b)

c)

d)

e)

f)

Figure 3. FTIR spectra of a) crystalline (black) and amorphous (grey) SVS; b) crystalline (black) and amorphous (grey) GBC; c) crystalline LYS (grey), crystalline SVS-LYS physical mixture (PM, black) and the corresponding co-amorphous mixture (CM, dashed); d) crystalline SER (grey), crystalline GBC-SER PM (black) and GBC-SER CM (dashed); e) crystalline THR (grey), crystalline GBC-THR PM (black) and GBC-THR CM (dashed); f) crystalline GBC-SER-THR PM (black), GBC-SER-THR CM (dashed) and calculated average spectra of GBC-SER CM and GBC-THR CM (grey).


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These findings indicate that with the drugs SVS and GBC, the drug-AA interactions were not found to be dependent on whether the AA came from the biological target site of the drug. This is an opposite finding to the previous study with drug-AA systems, where the drugs CBZ and IND formed strong intermolecular interactions only with AAs from their biological receptor21. This result indicates that the drug-AA interactions occurring at the receptor upon drug binding are different to those formed in the solid-state.

3.4. Stability studies The physical stability of the amorphous samples was tested during storage at 4°C/0%RH, ambient temperature/60% RH and 40°C/0% RH. As previously observed for SVS CM18, the pure amorphous SVS crystallized within a few days at elevated temperature (40°C/0% RH) and humidity (ambient/60% RH) and showed signs of recrystallization in XRPD at 58 days of storage at 4°C/0%RH (Figure 4a). These changes were in accordance with FTIR measurements (see Figure 5 in Supporting Information). In contrast, the co-amorphous SVS-LYS was much more stable, and was still X-ray amorphous after five months at 4°C/0%RH (Figure 4a, confirmed by FTIR (see Figure 6 in Suppelmentary data)). At elevated temperature (40°C/0% RH) this co-amorphous mixture showed signs of recrystallization within three months (the changes observed in FTIR spectrum were only minor at three months, see Figure 6 in Supporting Information). The stability advantage might be due to molecular mixing of SVS and LYS, since no stabilizing interactions were observed in FTIR (Figure 3b) and the Tg of this mixture was found to be only slightly higher than with SVS CM (Table 2).


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At elevated humidity (ambient/60% RH) the powder sample turned into a yellow waxy material within a few days, but interestingly, it did not show signs of recrystallization in XRPD until at day 56. Instead, FTIR showed clear signs of recrystallization already at 28 days in the carbonyl group absorption region (see Figure 6 in Supporting Information). The Tg of SVS-LYS CM was 9.3±1.2°C after two weeks of storage at elevated humidity which was much lower than the Tg of the original sample (33.2°C, Table 2). This indicates that the adsorbed moisture had transferred the system to a supercooled liquid at the storage temperature. In spite of this, the system remained mainly amorphous for at least 56 days. It can be concluded that the formation of co-amorphous mixtures provided a significant improvement against recrystallization in the case of SVS-LYS CM and GBC-SER CM and the stability was roughly correlated to the elevated Tg value. The co-amorphous mixtures did not show any signs for co-crystal formation upon recrystallization, but crystallized as pure individual components.

The XRPD results for the GBC samples stored at 40°C/0% RH are shown in Figure 4b (others shown in Supporting Information). GBC CM, GBC-THR CM and GBC-SER-THR showed recrystallization at five months, 40 days and three months, respectively, while GBC-SER remained amorphous for 6 months. At 4°C/0%RH, GBC CM showed the first small signs of recrystallization after five months of storage, GBC-SER CM was stable for six months, but GBC-THR CM and GBC-SER-THR CM showed clear signs of recrystallization at 44 days and three months, respectively. At elevated humidity (ambient/60% RH), GBC CM and GBC-SER CM showed signs of recrystallization at five months and GBC-THR CM and GBC-SER-THR CM had started recrystallizing, with the diffraction peaks present much earlier (at 26 days and


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three months, respectively). Furthermore, the AAs crystallized out first from the co-amorphous mixtures since the appearing peaks were located at the specific diffraction angles of the respective AA in the mixture (Figure 2a, Figure 4a-b). It was difficult to see differences in the spectra of the GBC formulations stored in different conditions, i.e. onset of crystallization was not evident based on FTIR. Interestingly, no time and/or condition dependent changes were observed in the tautomeric form of GBC in the co-amorphous mixtures, i.e. the amide form prevailed until crystallization (see Figures 6-9 in Supporting Information). In all cases, the presence of THR, which was shown to have a plasticizing effect on the mixture (Table 2) and not to interact to a notable extent, led to an earlier re-crystallization and a stability advantage provided by formation of co-amorphous mixtures was seen only with GBC-SER. GBC CM was found to be relatively stable in its individual amorphous form and the formation of a coamorphous system could only provide a slight improvement. This could be attributed to the absence of strong interactions between GBC and SER (Figure 3c) and a Tg value of the mixture similar to the Tg of GBC alone (Table 2). Overall, the stabilizing effect of the AAs on the amorphous drugs is probably due the AA molecules, which were able to interact with the drug to some extent (i.e. all except THR), disturbing the drug-drug interactions and thus delaying drug crystallization, as has been observed with sugar-vitamin systems.48. In all stored samples, the crystal forms that appeared were the same as for the raw materials.


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a)

b)

Figure 4. The XRPD diffractograms for a) amorphous SVS samples: I) SVS CM day 58 at 4°C/0% RH, II) SVS CM day 7 at ambient/60% RH, III) SVS CM day 7 at 4 0°C 0%RH, IV) SVS-LYS CM 5 months at 40°C 0%RH, V) SVS-LYS CM day 56 at ambient/60% RH and VI) SVS-LYS CM day 91 40°C 0%RH; b) amorphous GBC samples at 40°C 0%RH: I) GBC CM at 5 months, II) GBC-SER CM at 6 months, III) GBC-THR CM at day 40 and IV) GBC-SER-THR CM at 3 months.


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As a conclusion, in this study, co-amorphous drug-AA 1:1 mixtures were successfully prepared by cryomilling, using both AAs from the biological target site of the drugs and AAs not present there. It was observed that both types of AAs are able to form co-amorphous mixtures in which the stabilization of the amorphous state is based on disturbance of drug-drug interactions and thus delayed onset of crystallization rather than formation of strong drug-AA interactions. In this study, drug-AA interactions to small extent were observed. However, it should be considered that the interactions in a drug receptor involve not only one amino acid but often several different amino acids forming a binding pocket49. In the future, drug-target interaction modeling could be utilized in determining these binding pockets for a specific drug.

4

Conclusions

In this study, co-amorphous formulations of the drugs simvastatin (SVS) and glibenclamide (GBC) with amino acids (AAs) were prepared by cryomilling and their solid-state properties were investigated. Solid-state analysis by XRPD and DSC showed that SVS could only form a co-amorphous mixture with its receptor AA lysine (LYS), while GBC formed a binary coamorphous mixture with its receptor AA serine (SER) and the non-receptor AA threonine (THR), and a ternary co-amorphous mixture containing SER and THR. FTIR measurements did not reveal strong intermolecular interaction in these mixtures, however a positive effect on the tautomerism of amorphous GBC in the co-amorphous blends with SER and THR was seen, as the formation of the thermodynamically less stable imidic acid tautomer of GBC was suppressed compared to the pure amorphous drug. It can thus be seen that the presence of a receptor amino


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acid is not a strong prerequisite for the formation of co-amorphous mixtures and/or the formation of drug-AA intermolecular interactions. Nonetheless, the formation of co-amorphous mixtures provided a physical stability advantage over the amorphous drugs alone. SVS-LYS was found to be stable for three months when stored at 40°C/0% RH whereas GBC-SER was found to be stable for six months in these conditions. One stabilizing factor for GBC might be the hindrance of the conversion into its imidic acid tautomer upon formation of the amorphous form in the presence of AAs. This is an interesting finding as an interference with tautomeric structures has not been reported so far for co-amorphous systems. On the other hand, the AAs might disturb drug-drug interactions and thus delay the crystallization. On a general basis, this study confirms the assumption that amino acids generally are promising excipients for the formation of coamorphous mixtures.

AUTHOR INFORMATION Corresponding Author Riikka Laitinen, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C (P.O. Box 1627), FI-70211 Kuopio, Finland; Email: [email protected]; Tel: +358 50 569 5303 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENT RL thanks The Finnish Cultural Foundation North-Savo Regional Fund for financial support.


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Amino Acids as Co-amorphous Excipients for Simvastatin and

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