Investigation of DrugâExcipient Interactions in Biclotymol Amorphous

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Investigation of Drug-Excipient Interactions in Biclotymol Amorphous Solid Dispersions Benjamin Schammé, Nicolas Couvrat, Vincent Tognetti, Laurent Delbreilh, Valérie Dupray, Eric Dargent, and Gérard Coquerel Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00993 • Publication Date (Web): 12 Jan 2018 Downloaded from http://pubs.acs.org on January 14, 2018

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Molecular Pharmaceutics

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Investigation of Drug-Excipient Interactions in

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Biclotymol Amorphous Solid Dispersions

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Benjamin Schammé † §, Nicolas Couvrat †, Vincent Tognetti ‡, Laurent Delbreilh § *, Valérie

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Dupray † *, Éric Dargent §, Gérard Coquerel †

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† Normandie Univ, UNIROUEN, Sciences et Méthodes Séparatives, 76000, Rouen, France

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§ Normandie Univ, UNIROUEN, INSA Rouen, CNRS, Groupe de Physique des Matériaux,

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76000 Rouen, France

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‡ Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, 76821 Mont-Saint-

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Aignan, France

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* Corresponding authors: [email protected]. Tel: +33 2 32 39 90 82 (V.D.) [email protected]. Tel: +33 2 32 95 50 84 (L.D.)

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ACS Paragon Plus Environment

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Table of Contents Graphic

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Abstract

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The effect of low molecular weight excipients on drug-excipient interactions, molecular mobility

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and propensity to recrystallization of an amorphous active pharmaceutical ingredient is

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investigated.

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Pentaacetylglucose), five different drug:excipient ratios (1:5, 1:2, 1:1, 2:1 and 5:1, w/w) and

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three different solid state characterization tools (Differential Scanning Calorimetry, X-Ray

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Powder Diffraction and Dielectric Relaxation Spectroscopy) were selected for the present

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research. Our investigation has shown that the excipient concentration likewise with its

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molecular structure reveal quasi-identical molecular dynamic behavior of solid dispersions

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above and below the glass transition temperature. Across to complementary quantum

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mechanical simulations, we pointed out a clear indication of a strong interaction between

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Biclotymol and the acetylated saccharides. Moreover, the thermodynamic study on these

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amorphous solid dispersions highlighted a stabilizing effect of α-Pentaacetylglucose regardless

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its quantity while an excessive concentration of β-Pentaacetylglucose reveal a poor

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crystallization inhibition. Finally, through long-term stability studies, we also showed the

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limiting excipient concentration needed to stabilize our amorphous API. Herewith, the developed

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procedure in this paper appears to be a promising tool for solid-state characterization of

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complex pharmaceutical formulations.

Two

structurally

related

excipients

(α-Pentaacetylglucose

and

β-

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Keywords

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Amorphous Solid Dispersion; Molecular Mobility; Dielectric Spectroscopy; Physical Stability;

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Biclotymol; Excipients; Density Functional Theory

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Introduction

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Formulation procedures involve the presence of crystalline matter, in particular in the pharmaceutical

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industry.1 Active substances currently developed have become more and more complex, with a

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decreasing solubility. Indeed, over half of potential new pharmaceuticals exhibits poor water

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solubility leading to a limited bioavailability.2 As this proportion is likely to increase, improving the

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biodisponibility of these new drugs presents a significant technological challenge for pharmaceutical

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scientists.3–6 Numerous strategies have been devised and put forward in order to transform a

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crystalline drug into a more soluble counterpart.7,8 Among them, formulation of amorphous solids is

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a promising one.9–12 In opposition to the three-dimensional order of crystalline matter, amorphous

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solids are the most energetic solid state of a material and result in higher dissolution rate.13 However,

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the higher free energy of amorphous compounds is accountable for inherent thermodynamic

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instability14 including structural relaxation and nucleation/crystal growth that may arise during

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storage or dissolution in the human organism.15,16 Indeed, during their storage, amorphous states (as

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well as metastable states) may undergo unintended transformations to stable crystalline forms,

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altering their therapeutic properties in an uncontrolled manner.17 Consequently, keeping the benefits

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and promoting the use of amorphous compounds in pharmaceutical formulations requires a correct

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mastering of the amorphous state along with innovative approaches to extend its lifetime.18

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In this sense, stabilization of amorphous active substances is of particular interest to the

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pharmaceutical industry.19–26 Among suppression of crystallization of labile Active

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Pharmaceutical Ingredients (APIs), preparation of homogeneous dispersions are often conducted

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with a thorough complex mix of an active substance and excipient.27–31 A miscible solid

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dispersion of a drug and an additive is set as a unique chemically homogeneous phase where all

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components are narrowly mixed at the molecular level.32 From there, properties of the formulation

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are different from the properties of the pure components. Crystallization of the pharmaceutical


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ingredient into the blend can generate non-miscibility as the drug is in a separate crystalline state.

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Moreover, a resulting phase separation could be demonstrated by two existing amorphous phases.

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Felodipine, for instance, is completely miscible with polyvinylpyrrolidone (PVP)33 allowing an

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inhibition of crystallization while with poly acrylic acid, the system tends to effortlessly crystallize

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due to a partial miscibility.34

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Experimental studies reported that association of an active pharmaceutical ingredient with specific

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excipients such as antiplasticizers, surfactants or polymers could yield to an amorphous solid

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dispersion with a greater resilience to crystallization during downstream operations and storage. Over

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several years, polymers have been shown to modify solid-state crystallization of amorphous APIs

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arising from their stabilizing effect.35,36 This stabilization stems from several possible explanations

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including specific polymer-drug interactions, destabilization of drug interactions or reduction of

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molecular mobility. Since crystallization has a complex character, all these mechanisms together

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must be viewed as a whole: stabilization effect cannot be attributed to a single mechanism. Among

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the polymer class, plenty of them own a high glass transition temperature typically greater than

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100 °C. Thus, a high Tg polymer combined with a drug with a low Tg, ensures a higher glass

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transition temperature as it obeys to the Gordon Taylor law.37 Moreover, a higher glass transition

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temperature might result in a lower tendency to recrystallize. Indeed, addition of a polymer can act as

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an antiplasticizer; molecular mobility of the amorphous drug would therefore be limited. Restrained

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drug molecules would not be able to generate a stable nucleus, limiting crystallization outcomes. Yet,

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increase of Tg of the solid dispersion could not be considered as the main factor preventing

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crystallization since studies indicated that inhibiting crystallization could be accomplished even when

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Tg is not decreased or affected.38,39 It therefore appears that specific molecular interactions between

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APIs and excipients exist and could be accountable for stabilization of amorphous active

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pharmaceuticals.


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The significance of specific interactions between the amorphous state of a drug and an additive has

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also been broadly discussed in the background of crystallization from an amorphous matrix. On the

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basis of Fourier Transform Infrared (FTIR) and Raman spectroscopies, Indomethacin and

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Polyvinylpyrrolidone were shown to interoperate through intermolecular hydrogen bonding.40 It was

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postulated that drug / polymer hydrogen bonding interactions were relevant for stabilizing

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amorphous Indomethacin by disorganizing Indomethacin dimer’s self-association, even at low

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polymer concentrations where the antiplasticizing effect of the polymer is minimal. Likewise, FTIR

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analyses along with theoretical calculations have attested the presence of molecular interactions of

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hydrogen bonding type between Celecoxib and Polyvinylpyrrolidone.41

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More recently, the research work of Paluch and co-workers evidenced the considerable potential of

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low molecular weight excipients as carbohydrate derivatives with acetate groups (i.e. acetylated

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saccharides) to enhance the physical and chemical stability of amorphous drugs.42–52 Although

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several parameters are relevant for stabilization of amorphous dispersions, the group of Prof. Paluch

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indicated that the glass transition temperature might not be the only criterion for ensuring long-term

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stability of amorphous API in binary systems and highlighted the formation of inter and

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intramolecular interactions in the formed solid dispersions. However, despite examples of promising

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results between possible interaction among excipients and an amorphous drug, there can be specific

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cases where no particular interaction is observed between the amorphous drug substance and the

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excipient; physical stability could therefore be accounted to kinetic factors.

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As of now, a rationalization of interactions for APIs/excipients was still not reached due to the low

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number of molecular compounds analyzed. With this in mind, this current study investigates the

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effect of low molecular weight excipients on stabilization mechanism, molecular mobility and

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the inclination to recrystallization of amorphous Biclotymol. This active pharmaceutical


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ingredient which is used for the treatment of otolaryngology infections has been subject to

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several studies regarding its crystallization kinetics and stability.53,54 To investigate Biclotymol

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amorphous solid dispersions, we selected series of acetylated saccharides namely α-

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Pentaacetylglucose (α-acGLU) and β-Pentaacetylglucose (β-acGLU) (Figure 1). A specific

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feature of these two low molecular weight excipients is their chemical structure. When compared

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to non-modified saccharides, acetylated derivatives are found to possess acetyl groups instead of

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hydrogen atoms. As a matter of fact, this substitution towards acetyl groups has a significant

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influence on intermolecular interactions: non-modified glucose is a strongly associating liquid

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whereas acetylic systems are typical Van der Waals liquids. Acetylated derivatives are rich in

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oxygen which is a good acceptor for hydrogen bonds, but do not have proton donors. Therefore,

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acetylated derivatives cannot create hydrogen bonds on their own.

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To do so, impact of components concentration, molecular structure and size of the excipient and

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attainable interactions onto the molecular dynamics of the amorphous drug dosage were

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regarded. Then, for the purpose of selecting the appropriate API-excipient blend, critical

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characteristics of components are examined to provide insights into stabilization mechanisms as

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well as the impact of intermolecular interactions on the life expectancy of amorphous

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formulations.

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Experimental Methods

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Materials

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Biclotymol (C21H26Cl2O2, Mw = 381.32 g/mol) received as a crystalline white powder was kindly

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provided by Pharmasynthese (Inabata Group). No impurity was detected under high performance

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liquid chromatography-sustained conditions. The compound was consequently used without


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prepurification. An X-ray pattern of commercial Biclotymol was recorded and revealed a

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completely anhydrous crystalline form, in agreement with Rantsordas et al. (Cambridge

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Structural Database (CSD-MYCMPP).55 This Active Pharmaceutical Ingredient (API) exists in

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two crystalline varieties, one stable (Form I) and one metastable (Form II) in a monotropic

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relationship.56,53,57,54 α-Pentaacetylglucose (α-acGLU, C16H22O11, Mw = 390.34 g/mol) with

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purity greater than 99% was purchased from Sigma-Aldrich whereas β-Pentaacetylglucose (β-

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acGLU, C16H22O11, Mw = 390.34 g/mol) with purity greater than 98% was purchased from Alfa

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Aesar. These two compounds were used without prepurification. Developed formulae of

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Biclotymol, α-Pentaacetylglucose and β-Pentaacetylglucose are shown in Figure 1.

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Figure 1. Developed formulae of the Biclotymol molecule (A) and Haworth projection of

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chemical structures of α-Pentaacetylglucose (B) and β-Pentaacetylglucose (β-acGLU) (C).

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Preparation of Amorphous Systems

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The amorphous Biclotymol, α-Pentaacetylglucose (α-acGLU) and β-Pentaacetylglucose (β-

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acGLU) as well as binary systems with different weight fractions of acetylated saccharides were

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prepared by the quench cooling technique. In order to obtain homogeneous Biclotymol-

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acetylated saccharide solid dispersions, crystalline powders of both compounds were first


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thoroughly mixed by hand mortar and pestle milling for five minutes (operation was repeated

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twice). Crystalline mixtures were fully melted (Tm Biclotymol = 125.6 °C, Tm α-acGLU = 112.6 °C, Tm β-

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acGLU

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metal crucible to a very cold metal plate. Heating rates were only of 10 K/min while cooling

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rates were always greater than 50 K/min, with a time spent in the melt of two minutes.

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No separation, cracks or heterogeneity of the sample have been detected. Only completely

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amorphous samples obtained in this way were analyzed immediately after preparation to protect

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them from atmospheric moisture and any structural changes. A total of ten mixtures of

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Biclotymol with acetylated saccharides were investigated. For each excipient (α-acGLU and β-

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acGLU), various weight ratios as 5:1, 2:1, 1:1, 1:2 and 1:5 were prepared. The first number

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corresponds to the weight ratio of Biclotymol whereas second number corresponds to the weight

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ratio of excipients (α-acGLU or β-acGLU).

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= 131.2 °C) and quenched either in-situ inside the DSC pan or ex-situ by a transfer of a

Dielectric Relaxation Spectroscopy (DRS)

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Measurements were carried out in a frequency range of 10−2 – 2.106 Hz with a Novocontrol

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Alpha Analyzer. Dielectric spectra were collected over a wide temperature range from -140 to

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100 °C, with appropriate successive steps. Accurate temperature control was implemented using

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the Quatro system (Novocontrol Technologies), allowing a temperature stability of ± 0.2 °C.

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Amorphous solid dispersions were analyzed using high-quality interdigitated electrodes from

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Novocontrol Technologies (sensor diameter 20 mm, gold-plated copper combs) as previously

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outlined in other papers.58–60

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X-ray Powder Diffraction (XRPD)

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XRPD analyses of solid mixtures were recorded on a benchtop INEL Equinox 100

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diffractometer, mounted with a copper micro focus tube (λ = 1.541 Å), equipped with a curved

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detector. The acquisitions are performed by reflexion in real time up to 110° in 2θ, at 40 kV, 10


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mA with a metal rotating sample holder. A spinning sample holder has been used to overcome

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preferential crystallization effects (Ø 15 mm in diameter and Ø 0.5 mm in thickness). XRPD

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duration was of 10 min and performed directly after the production of samples.

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Temperature-Modulated Differential Scanning Calorimetry (TM-DSC)

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The thermodynamic properties of solid dispersions were investigated by the TM-DSC technique.

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Calorimetric measurements were performed on a Q2000 DSC instrument (TA Instruments)

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coupled with a liquid-nitrogen cooling system. Temperature and enthalpy calibrations were

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carried out with both indium and benzophenone standards. Specific heat capacities were

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measured using sapphire as a reference. Baseline was calibrated from -20 to 200 °C, with an

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oscillation amplitude of ± 0.318 K, an oscillation period of 60 s, and a heating rate of 2 K/min

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used in the experiments. The samples (5.00 ± 0.05 mg) were enclosed in sealed hermetic

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aluminum pans Tzero, and the atmosphere was regulated by a nitrogen flow (50 mL/min).

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Raman Spectroscopy

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Raman analyzes were carried out with a Confocal Raman microscope (LabRam HR by Jobin-

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Yvon Horiba) coupled to an optical microscope (model BX41, Olympus) with xyz mapping

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stage. The excitation of Raman scattering was operated by a He-Ne laser at a wavelength of

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632.8 nm. The laser beam was focused on the sample by a microscope objective X50. The

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confocal pinhole was of 200 µm diameter. The Raman signal was analyzed using a 600 lines per

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mm grating and a spectrometer slit of 100 µm. A 25 µm x 25 µm area was analyzed by steps of 1

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µm. The resolution was estimated to 0.5 µm in (X,Y) and 9 µm in (Z). An exposure time of 15 s

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was used to record the Raman Spectra over the wavenumber range 2700-3200 cm-1 with a one-

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time accumulation. The duration of the data collection was adjusted in order to minimize the

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background signal.

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Computational details

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Theoretical calculations for molecular interactions of Biclotymol-α-acGLU and Biclotymol-β-

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acGLU were performed within the framework of density functional theory (DFT) using the

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Gaussian 09 package.61 The initial geometries for the isolated molecules were obtained from the

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respective crystalline structures of Biclotymol, α-Pentaacetylglucose (α-acGLU) and β-

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Pentaacetylglucose (β-acGLU), and were optimized with the dispersion corrected B97D exchange-

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correlation functional.62 Forty structures for the bimolecular complexes (twenty for the Biclotymol-

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α-acGLU and twenty for Biclotymol-β-acGLU) were generated using our own fully quantum

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simulated annealing63, based on high temperature semi-empirical PM6 molecular dynamics

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simulations, followed by root-mean-square deviation (RMSD) filtering and a subsequent DFT

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optimization with small basis sets, finally completed by a second RMSD filtering before final

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optimization at the high level of theory, for which the following basis set combination was

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chosen: 6-31+G(d) for Cl and O, 6-31G(d) for C and H. The nature of stationary points were

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checked by vibrational analysis (harmonic frequencies). Complexation energies, Ecomplexation,

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were calculated as Ecomplexation = E(AB) - E(A)opt - E(B)opt with E(AB) the energy of the complex

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A…B, and E(A)opt that for the optimized fragment A with the basis functions centered on A.

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Interaction energies, Einteraction, were corrected for basis set superposition error using the standard

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Boys−Bernardi counterpoise method64: Einteraction = E(AB) - EA…B (A) - EA…B (B) with EA…B (A)

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the self-consistent field (SCF) energy of fragment A with the full basis of A and B at the

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geometry A takes in the complex. Gibbs energies were evaluated using standard statistical

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physics formula based on the ideal gas partition function. However, in order to better describe

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entropy in condensed phase, all contributions for rotational and translational entropies were

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removed since mobility in such phases is considerably reduced.

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Results and Discussion

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Structural and Thermodynamic Characterization of Amorphous Solid Dispersions

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The first part of this section is dedicated to the safe preparation (without thermal decomposition)

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of amorphous acetylated saccharides alone and solid dispersions formed between acetylated

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saccharides and Biclotymol by quench cooling from the melt. Thermogravimetric measurements

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were carried on the commercial crystalline forms to check whether these compounds undergo

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thermal degradation during the melting process. We checked that the melting endotherms of the

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crystalline forms of α-acGLU (Tm α-acGLU = 112.6 °C) and β-acGLU (Tm β-acGLU = 131.2 °C) are

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located far from the range of their thermal decomposition. TGA curves indicate that the onset of

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thermal decomposition of α-acGLU and β-acGLU begins above 155 °C (see Figure S1,

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Supporting Information). Besides, Biclotymol (Tm Biclotymol = 127 °C) exhibits no degradation up

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to 180 °C.53 Therefore, these results show that melting the crystalline forms of Biclotymol as

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well as acetylated saccharides and preparing various amorphous compositions based on both

240

compounds by vitrification from cooling the melt is safe. Moreover, it should be noted that the

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melting temperatures of Biclotymol and derived saccharides are very similar. Mixing of

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compounds in their liquid states could thus be promptly performed without the hazard of

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components overheating. A merely simple observation shows the creation of homogeneous

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solutions, in any weight ratio. It is worth noting that preparation of the solid dispersions by

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quench cooling of the melt does not consume a lot of time and does not require using any

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additional solvents in contrast to the other amorphous binary mixtures prepared for instance by

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the solvent evaporation and precipitation techniques. In order to confirm the amorphous nature of

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quench-cooled acetylated saccharides, the XRPD technique was applied. Figure 2 demonstrates

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that Biclotymol, α-acGLU and β-acGLU can be transformed into amorphous solids with the

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selected procedure.


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Figure 2. X-Ray powder diffraction patterns obtained for α-acGLU (blue line), β-acGLU (red

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line) and Biclotymol (purple line) (A) before melt-quenching and (B) after melt-quenching.

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Beam cut-off was located close to 6.5° (2θ).

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Amorphous nature of these excipients was also confirmed using TM-DSC analyses. Figure 3

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(upper black curves) shows the sharp endothermic events corresponding to the melting process

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of the commercial stable crystalline forms. After quenching from the melt, a subsequent

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temperature-modulated DSC heating scan from the glassy state reveals well-defined Cp jumps.

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For α-acGLU and β-acGLU, exothermic events are noticed corresponding to the emerging cold

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crystallization. At higher temperatures, it is followed by sharp endothermic event corresponding

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to the melting of the crystalline form obtained beforehand.


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Figure 3. TM-DSC measurements of crystalline and amorphous forms of Biclotymol (top panel),

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α-acGLU (left panel) and β-acGLU (right panel). (1) Melting of the commercial stable form, (2)

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glass transition region, (3) crystallization of the supercooled melt to the crystalline form, (4)

266

melting of the crystalline form.

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It is remarkable that both pentaacetyl derivatives (differing only in location of the acetyl group

268

attached to the first carbon in the sugar ring), α-acGLU and β-acGLU, possess different

269

crystallization tendencies but practically the same values of Tg, fragilities and molecular

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dynamics as highlighted by a recent study of Kaminski and coworkers.42 This enabled these

271

authors to postulate that, except for kinetic and thermodynamic factors, molecular conformation

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may play an important role in controlling crystallization abilities of glass-formers.


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To confirm the homogeneity of prepared amorphous solid dispersions, confocal Raman

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spectroscopy has been applied. In recent years, Raman mapping has been effectively applied to

275

amorphous drug systems thanks to its high-spatial resolution.65,66 In this sense, spatial

276

distribution of chemical species can be attained. In the framework of Biclotymol and acetylated

277

saccharides solid dispersions, Raman spectrum analysis for characteristic bands associated with

278

Biclotymol and α-acGLU / β-acGLU was performed. We selected the characteristic band of

279

amorphous Biclotymol located at 2871 cm-1 as well as the one of acGLU and β-acGLU at 2939

280

cm-1 (see Figure S2, Supporting Information). Raman mapping for all ten mixtures, measured at

281

room temperature, showed homogeneous distribution in the selected wavenumber region,

282

attesting the uniformity of our amorphous solid dispersions.

283 284

Figure 4 presents diffraction patterns of the physical mixtures after melt-quenching. In the case

285

of the Biclotymol - α-acGLU mixtures no Bragg peaks are visible. Instead, broad amorphous

286

halo patterns characteristic of materials having no long-range three-dimensional molecular order,

287

were obtained. The crystalline Biclotymol fraction is not visible for compositions 2:1 and 5:1

288

(i.e. enriched in Biclotymol) while it was clearly observed in the XRPD patterns of the

289

crystalline mixtures (see Figure S3, Supporting Information). On the other hand, a totally

290

different scenario was noticed for Biclotymol - β-acGLU mixtures. In Figure 4 (right panel),

291

sharp Bragg peaks are present indicating the presence of crystals in the investigated samples.

292

However, Bragg peaks are only observable for physical mixtures of 1:2 and 1:5 ratios of

293

Biclotymol - β-acGLU. With a closer scrutiny on Figure 4 (right panel), characteristic Bragg

294

peaks of crystalline β-acGLU can be retrieved while no Bragg peaks of crystalline Form I or

295

Form II of Biclotymol can be seen (see Figure S4, Supporting Information). However, one

296

cannot rule out the potential presence of a low fraction of crystallized Biclotymol in the solid


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dispersions, non-detectable by XRPD. Therefore, for enriched compositions in β-acGLU, the

298

resulting mixture seems to possess fast kinetics of crystallization towards the stable crystalline

299

form of β-acGLU, although XRPD have been recorded immediately after quenching.

300 301

Figure 4. X-ray Powder Diffraction patterns for melt-quenched representative mixtures: (left

302

panel) melt-quenched Biclotymol-α-acGLU and (right panel) melt-quenched Biclotymol-β-

303

acGLU. XRPD analysis was performed directly after the production of samples.

304

One prominent feature in the use of stabilizers is the possibility to suppress a potential

305

crystallization phenomenon. Figure 5 shows TM-DSC measurements recorded upon heating

306

fused-quenched mixtures. For Biclotymol - α-acGLU system, only one endothermic event

307

associated with the glass transition is noticed within the whole examined temperature range. No

308

additional event that could indicate an exothermic cold crystallization or the presence of

309

heterogeneity (segregation) in the sample was observed. Therefore, the non-occurrence of cold-

310

crystallization whatever the temperature, is an indication of the increased stability of amorphous

311

Biclotymol. Conversely, in Figure 5 (right panel), solid dispersions of 1:2 and 1:5 ratios of

312

Biclotymol - β-acGLU are characterized by a strong tendency toward cold-crystallization to the


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313

crystalline form of β-acGLU. The enthalpy of the exothermal processes increases with the

314

percentage of β-acGLU (∆Hc 1:2 = 25.4 J/g and ∆Hc 1:5 = 42.1 J/g) which seems to be in line with

315

our previous analyses. Solid dispersions of Biclotymol with the two investigated acetylated

316

disaccharides attest the presence of a single glass transition event, regardless the excipient’s

317

weight ratio. Besides, values of the glass transition temperatures for all investigated solid

318

dispersions are nearly the same, as attested by reversing heat capacity values of solid dispersions

319

(see Figures S5 and S6, Supporting Information). This finding is not surprising because even

320

tough amorphous solid dispersions conform to a Gordon-Taylor law, the Tg of pure components

321

are very similar.

322 323

Figure 5. TM-DSC thermograms obtained for melt-quenched Biclotymol-α-acGLU (left panel)

324

and melt-quenched Biclotymol-β-acGLU (right panel) solid dispersions during heating.

325

The structural (XRPD) and thermal (TM-DSC) findings presented above seem to indicate that

326

the amorphous solid dispersions exhibit a very different behaviour between the two selected

327

excipients in the presence of Biclotymol. In one case, there is no crystallization of either

328

Biclotymol and α-acGLU in the Biclotymol- α-acGLU solid dispersions while for Biclotymol-β-

329

acGLU, crystallization of β-acGLU occurs for 1:2 and 1:5 ratios. However, even if no trace of


16

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330

crystalline Biclotymol has been seen in above experiments, its presence cannot be totally

331

excluded. It might be argued that the difference between Tm and Tg could have a potential impact

332

on the evolution of the crystallization driving forces. In the same way, position of the maxima of

333

nucleation and growth of the solid dispersions made with either α-acGLU or β-acGLU will be

334

constrained differently due to the Tm - Tg difference.

335

To monitor the stability of amorphous solid dispersions, new freshly samples were prepared,

336

stored under normal conditions of use and structurally analyzed (Figure 6). It has been found that

337

for the highest concentration of acetylated saccharides (i.e. 1:2 and 1:5), presence of crystalline

338

α-acGLU (Figure 6, left panel) and β-acGLU (Figure 6, right panel) is still noticeable after four

339

months of storage. This is also the case for solid dispersions enriched in Biclotymol (i.e. 5:1)

340

where crystalline Form I of Biclotymol is detectable. In these two specific cases, one can note

341

the valuable information that recrystallization of Biclotymol toward its metastable Form II could

342

be inhibited by addition of modified saccharides. Thus, the right mixing ratio would be a drug

343

loading of Biclotymol two times larger than the selected excipient (ratio of 2:1) as no

344

crystallization was highlighted for both excipients.


17


Page 18 of 50

345 346

Figure 6. X-ray Powder Diffraction patterns for melt-quenched representative mixtures after 4

347

months of storage at 293 K, 30% RH: (left panel) melt-quenched Biclotymol-α-acGLU and

348

(right panel) melt-quenched Biclotymol-β-acGLU.

349

Molecular Dynamics of Amorphous Solid Dispersions

350

Various features can play a role on the stabilization mechanisms of amorphous materials. Among

351

them molecular mobility is widely considered.67 To characterize the molecular dynamics of our

352

amorphous solid dispersions at several temperatures, dielectric measurements were completed. It

353

has been proven in recent years that this experimental procedure provides a precise investigation

354

of glass-forming systems by looking at relaxation processes at temperatures lower and higher

355

than the glass transition temperature.68–71

356

Figure 7, Figure 8 and Figure 9 display selected dielectric spectra for pure Biclotymol, α-acGLU,

357

β-acGLU and as well as their representative amorphous solid dispersions.


18

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358 359

Figure 7. Imaginary (ε″) parts of the complex dielectric permittivity vs frequency in the glassy

360

(T < Tg) and supercooled liquid states (T > Tg) for (a) pure α-acGLU, (b) β-acGLU and (c) pure

361

Biclotymol. Left vertical axe corresponds to the imaginary permittivity of the α-process while

362

right vertical axe represents the γ-process.


19


Page 20 of 50

363 364

Figure 8. Dielectric loss spectra of representative amorphous solid dispersions between

365

Biclotymol and α-acGLU, analyzed above and below Tg. (a) Biclotymol - α-acGLU 1:5 (b)

366

Biclotymol - α-acGLU 1:2 (c) Biclotymol - α-acGLU 1:1 (d) Biclotymol - α-acGLU 2:1 (e)

367

Biclotymol - α-acGLU 5:1. Left vertical axe corresponds to the imaginary permittivity of the α-

368

process while right vertical axe represents the γ-process.


20

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369 370

Figure 9. Dielectric loss spectra of representative amorphous solid dispersions between

371

Biclotymol and β-acGLU, analyzed above and below Tg. (a) Biclotymol - β-acGLU 1:5 (b)

372

Biclotymol - β-acGLU 1:2 (c) Biclotymol - β-acGLU 1:1 (d) Biclotymol - β-acGLU 2:1 (e)

373

Biclotymol - β-acGLU 5:1. Left vertical axe corresponds to the imaginary permittivity of the α-

374

process while right vertical axe represents the γ-process.


21


Page 22 of 50

375

Key characteristics can be monitored: at low frequencies, dc-conductivity can be identified.

376

Moving toward higher frequencies, the structural α-relaxation associated with the dynamic glass

377

transition can be observed. These two phenomena were found to shift toward lower frequencies

378

upon cooling. In addition, below Tg, in the glassy state, one distinct secondary relaxation

379

(denoted γ-relaxation) was noticed for pure Biclotymol, α-acGLU, β-acGLU as well as for the

380

amorphous solid dispersions. As emphasized in Figure 7, Figure 8 and Figure 9, dielectric

381

spectra obtained illustrate the uniformity of all of our amorphous solid dispersions since one

382

single clearly discernible α-relaxation was highlighted. In addition, no Maxwell-Wagner

383

relaxation process (often emerging in phases separating systems) was detected along all our

384

blends, further confirming the overall homogeneity of as-prepared solid dispersions.72 Besides,

385

additional analysis of structural relaxation loss peaks across the one-sided Fourier transform of

386

the Kohlrausch−Williams−Watts (KWW)73 function revealed that stretching parameter βKWW

387

remains steady over the entire temperature range (βKWW

388

temperature has nearly no impact on the shape of the α-relaxation process but once more confirm

389

the uniformity of our amorphous blends (see Figure S7, Supporting Information).

mean value

= 0.62). This highlights that

390 391

Primary and secondary relaxations of pure compounds and amorphous solid dispersions were

392

analyzed by means of a single Vogel-Fulcher-Tammann74–76 (VTF) and an Arrhenius equation,

393

respectively (detailed description of the data fitting can be found in Supporting Information).

394

Determined relaxation times were plotted as a function of the inverse of the temperature as

395

displayed in the relaxation map in Figure 10 (temperature dependence of the fit parameters αHN

396

and βHN as well as enlarged view of the caption can be seen in Figures S8, S9 and S10). From the

397

estimated parameters of VTF fits, Tg can be readily estimated at dielectric relaxation time τα =

398

100 s (Table 1). It should be emphasized that all primary α-relaxation processes lie in the same


22

Page 23 of 50 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


399

temperature region, highlighting almost identical Tg values as well as the fragility component,

400

regardless of the selected excipient. Taking into account errors on fragility values, we could

401

consider that such a parameter is concentration-independent. Moreover, Tg values obtained by

402

DRS are somewhat lower compared to those obtained from TM-DSC measurements but are in

403

accordance with the value of Tg for τα = 10 s (corresponding to the equivalent frequency of the

404

TM-DSC analysis).77

405 406

Figure 10. Relaxation map of pure Biclotymol, pure α-acGLU, pure β-acGLU and amorphous

407

solid dispersions. Solid gray lines are the VTF fits to the of structural α-relaxation times,

408

illustrated by filled symbols. Temperature dependence of the secondary γ-relaxations is

409

illustrated by open symbols and was fitted by the Arrhenius equation.

410

Table 1. Glass transition temperatures (Tg) of pure Biclotymol and pure excipients (α-acGLU

411

and β-acGLU) determined from TM-DSC and DRS, fragilities obtained from DRS data and


23


Page 24 of 50

412

activation energy barriers Ea γ of the secondary relaxation observed in solid dispersion blends.

413

The uncertainty of the glass transition temperatures is ± 1 K while errors for fragility and

414

activation energies is of 10 %, standard error for polymers.78

Sample

Tg from TM-DSC (in K)

Tg from DRS (in K) (τα = 10 s)

Tg from DRS (in K) (τα = 100 s)

Fragility (from DRS)

Pure Biclotymol Pure α-acGLU Pure β-acGLU

293 290 294

293 286 292

290 283 288

88 97 85

Activation energy barriers of γrelaxation (in kJ/mol) 75.3 45.3 42.5

Biclotymol- α-acGLU 1:5 Biclotymol- α-acGLU 1:2 Biclotymol- α-acGLU 1:1 Biclotymol- α-acGLU 2:1 Biclotymol- α-acGLU 5:1

289 291 293 295 297

287 289 292 294 295

284 286 289 290 291

91 89 94 91 84

41.2 43.7 39.2 49.2 35.3

Biclotymol- β-acGLU 1:5 Biclotymol- β-acGLU 1:2 Biclotymol- β-acGLU 1:1 Biclotymol- β-acGLU 2:1 Biclotymol- β-acGLU 5:1

293 292 293 295 293

290 290 291 294 294

287 287 288 291 291

86 87 92 87 85

41.9 38.5 48.4 43.2 31.3

415 416

In order to analyze the progress of crystallization, the temperature dependence of the dielectric

417

strength (∆εα) of the α-relaxation versus temperature for all examined amorphous solid

418

dispersions as well as pure components was outlined in Figure 11. As defined by Onsager,

419

Fröhlich, and Kirkwood equation72, by increasing the temperature, the dielectric relaxation

420

strength ∆εα decreases for all samples.72,79 Similar trends can be seen for other glass-forming

421

systems as polymers80 and pharmaceutical substances.81

422 423

Interestingly, by contrast to similar glass transition temperatures obtained for all mixtures,

424

dielectric strength values for solid dispersions do not follow a classical mixing rule. As shown in

425

Figure 11 a), the dielectric strength of Biclotymol-α-acGLU amorphous solid dispersions is

426

relatively high and clustered around ∆εα = 8 to 11, except for the blend with an enriched


24

Page 25 of 50 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


427

Biclotymol composition which is consistently closer to pure Biclotymol. Relating to Biclotymol-

428

β-acGLU amorphous solid dispersions in Figure 11 b), blends made of 1:1, 2:1 and 5:1 possess

429

the same behavior pattern. In contrast, compositions enriched with excipients (1:2 and 1:5) have

430

lower ∆εα against other compositions. This certainly seems reasonable as the density of dipoles

431

involved in the relaxation process (i.e. amount of relaxing amorphous phase) should be falling

432

due to the onset of recrystallization of these formulations as displayed in Figure 5. This

433

difference in terms of ∆εα may originate from the spatial distribution of acetylated carbohydrates

434

with respect to Biclotymol molecules and may lead to a change of the strength of the

435

intermolecular interactions in amorphous solid dispersions.

436 437

Figure 11. Temperature dependence of the dielectric strength for α- relaxation (∆εα) versus

438

temperature for all investigated amorphous solid dispersions. Left panel a) corresponds to

439

Biclotymol-α-acGLU blends while right panel b) matches with Biclotymol-β-acGLU mixtures.

440

With reference to the glassy state of solid dispersions, pure Biclotymol demonstrates the highest

441

activation energy barrier Ea

442

Tripathi et al. (Ea = 75.5 kJ/mol).57 As for this API, the molecular origin of its secondary

443

relaxation was previously discussed. With the use of dielectric spectroscopy, Tripathi et al.

444

suggested a likely intramolecular secondary dynamic involving the hydrogen bonds formed by

γ-Biclotymol,

close to 75.3 kJ/mol in accordance with that found by


25


Page 26 of 50

445

the hydroxyl groups of Biclotymol. Pure acetylated saccharides, α-acGLU and β-acGLU, own

446

lower activation energy barriers of Ea

447

respectively. Those values are in the range determined by Kaminski et al.42 Addition of modified

448

saccharides, in whatever amount, give rise to a single secondary relaxation process. The

449

activation energy barriers ascertained for the γ-relaxations are comparable, within the range of 35

450

- 49 kJ/mol for Biclotymol-α-acGLU and 31 - 48 kJ/mol for Biclotymol-β-acGLU (Table 1).

451

These values are similar to the ones of pure α-acGLU and β-acGLU, suggesting the involvement

452

of the same molecular motions. Owing to their relatively low Ea values, secondary processes in

453

our solid dispersions originate most likely from an intramolecular origin. According to an earlier

454

study, this stems from the motion of acetyl sequences in modified carbohydrates.82 We can

455

therefore consider that the secondary relaxation process occurring in solid dispersions is linked

456

to intramolecular mechanisms associated with short-range intermolecular interactions within

457

Biclotymol and the selected excipient. This is supported by the relaxation map in Figure 10,

458

depicting that the secondary γ-relaxations show nearly no energy variations but rather

459

temperature changes, supporting the potential impact of intermolecular interactions in

460

amorphous mixtures. In addition to this, by taking into account the possible formation of

461

hydrogen-bonds between Biclotymol and the acetylated saccharides, one would think that the

462

intramolecular γ-relaxation could be inhibited if some these H-bonds are related to the molecular

463

parts able to generate the relaxation (at least for some of the pure components in the mixture).

γ-α-acGLU =

45.3 kJ/mol and Ea

γ-β-acGLU =

42.5 kJ/mol,

464 465

It seems clear from the above findings that molecular mobility of investigated amorphous solid

466

dispersions made of Biclotymol and pentaacetyl derivatives are very alike. Investigated

467

formulations reveal a homogenous character with a single structural mechanism along with a

468

unique noticeable secondary relaxation process for all blends. In this way, the observed


26

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469

discrepancies by XRPD and DSC between solid dispersions made with α-acGLU and β-acGLU

470

were not spotlighted by dielectric measurements, known to finely characterize the amorphous

471

state. Hence, the excipient concentration likewise with its molecular structure tends to reveal

472

quasi-identical molecular dynamic behavior of solid dispersions above and below the glass

473

transition temperature. This indicates that a crystalline environment composed of β-acGLU, in

474

the case of unstable solid dispersions 1:2 and 1:5 of Biclotymol - β-acGLU, does not impact the

475

resulting amorphous fraction in terms of molecular mobility. On the other hand, the

476

thermodynamic study on solid dispersions highlighted a stabilizing effect of α-acGLU regardless

477

its quantity while an excessive concentration of β-acGLU (blends 1:2 and 1:5) would promote an

478

inclination to recrystallization to the crystalline form β-acGLU and physical instability. The

479

difference here with regard to a classical stabilization protocol83 lies in the fact that selected API

480

(i.e. Biclotymol) and excipients (i.e. α-acGLU and β-acGLU) possess quasi-identical glass

481

transition temperature, very close to room temperature. Therefore, the obtained results would

482

suggest that in solid dispersions, the glass transition temperature is not the only factor for the

483

stabilization and that molecular interactions between API and excipient could yield to greater

484

resilience to devitrification. With this viewpoint, complementary quantum mechanical

485

simulations have been conducted.

486 487

Modelling of Amorphous Solid Dispersions

488

Quantum simulations happen to become increasingly popular in the pharmaceutical field,

489

especially due to its usefulness in the interpretation of vibrational spectra (for experimental band

490

assignment mainly)84 or for the validation of molecular structures by means of identification of

491

conformational minima.85 Indeed, a significant increase in the use of density functional theory

492

(DFT) has been recorded over the past decades in computational chemistry, from medium to


27


Page 28 of 50

493

large molecules, including pharmaceuticals.86–89 Therefore, we performed DFT calculations in

494

order to provide a more complete picture of the interactions between Biclotymol and selected

495

acetylated saccharides.

496

To this aim, an extensive sampling of the potential energy surface was performed, leading to the

497

location of many energy minima, which are collected in the supplementary information file

498

(Figures S11 and S12). The most stable optimized structures of Biclotymol-α-acGLU and

499

Biclotymol-β-acGLU systems are displayed in Figure 12. The most negative values for the

500

calculated complexation energies for both systems were very alike, with values of -91.1 kJ/mol

501

for Biclotymol-α-acGLU and -95.8 kJ/mol for Biclotymol-β-acGLU. Besides, interaction

502

energies (which do not take into account the deformation energy necessary to form the complex

503

from the isolated molecules at their energy minimum) are even closer since they equal -110.70

504

kJ/mol for Biclotymol-α-acGLU and -110.13 kJ/mol Biclotymol-β-acGLU.

505

These results provide a clear indication of a strong interaction between Biclotymol and the

506

acetylated saccharides. With respect to non-covalent interactions, a single hydrogen bond (C40-

507

O43...H65-C64) was noticed with a distance of 1.97 Å for Biclotymol-α-acGLU complexes (Figure

508

12 (A)), while two hydrogen bonds were found for Biclotymol-β-acGLU: one of intramolecular

509

origin (C54-O64…H67-O66 = 1.75 Å) and one of intermolecular nature (C44-O45…H65-O64) with a

510

distance of 1.85 Å (Figure 12 (B)), which could account for the very slight higher stability of the

511

dimer formed by β-acGLU. However, on account of their complexity, it has proved difficult to

512

achieve detection of Raman bands related to the new hydrogen bonds in the recorded spectra.


28

Page 29 of 50 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


513 514

Figure 12. Optimized structures of Biclotymol-α-acGLU (upper panel) and Biclotymol-β-

515

acGLU (lower panel) and corresponding complexation energies.

516

However, one should keep in mind that our DFT calculations, consistent with those in the

517

literature, were made on a ratio of one molecule of API with one molecule of excipient. Actually,

518

the hydrogen bonds network revealed by the DFT calculations suggests that collective effects

519

involving many molecules could be at stake, a behavior that fully unravel the drug loading effect

520

in the amorphous solid dispersions. Temperature certainly is an important factor to account for

521

the dynamics of these complexes. Even if our DFT calculations describe static properties,

522

temperature effects can actually be incorporated through the evaluation of standard Gibbs

523

complexation energies. Indeed, the most negative values were found to be equal to -93.7 kJ/mol

524

(Biclotymol-β-acGLU) and -109.9 kJ/mol (Biclotymol-α-acGLU). This not-negligible difference

525

can be ascribed to vibrational entropies (Svib), the –TSvib(AB) values amounting to -278.1 kJ/mol

526

and -287.5 kJ/mol, respectively. This indicates that even if interaction and complexation energies


29


Page 30 of 50

527

are almost identical, temperature-dependent properties could differ for the two mixings. This

528

could explain why the two systems could appear similar or different depending on the

529

experimental technics used to study them.

530

Conclusions

531

In this paper, amorphous solid dispersions formed by a series of low molecular weight

532

excipients, i.e. acetylated saccharides, and Biclotymol were investigated. Effect of these

533

excipients on drug-excipient interactions, molecular mobility and recrystallization outcomes

534

were considered. We have shown that homogeneous amorphous solid dispersions can be safely

535

prepared and analyzed by means of various experimental techniques and also investigated by

536

molecular modelling techniques. Our findings show that the molecular mobility above and below

537

the glass transition temperature cannot be considered as the only factor for stabilization of solid

538

dispersions. Indeed, the glass transition temperatures of the solid dispersions, irrespective of the

539

ratio, are very close, a feature that was related to very similar interaction and complexation

540

energies (close to 100 kJ/mol in absolute value) as revealed by density functional theory

541

calculations. In addition, stability study showed the limiting excipient concentration needed to

542

stabilize our amorphous API for several months under classical storage conditions. The results of

543

the above study acted as the basis for further analyses, in particular toward a deeper

544

characterization of other complex formulations of molecular alloys, structured by a network of

545

intramolecular and intermolecular hydrogen bonds, before and after the cold-crystallization for

546

instance.

547

Supporting Information Description

548

TGA analysis, Raman spectra, XRPD patterns, TM-DSC analyses, DRS spectra and fitting

549

procedure, molecular complexes simulated by DFT.


30

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550

Acknowledgement

551

The Region Normandie is acknowledged for financial support to B. S. via the E.D. No. 591

552

(PSIME). The authors would like also to acknowledge the high-performance computing facility

553

(CRIANN) funded by the Region Haute Normandie.

554

Author Contributions

555

The manuscript was written through contributions of all authors. All authors have given approval

556

to the final version of the manuscript.

557


31


558

References

559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604

(1) (2)

(3) (4)

(5)

(6)

(7)

(8) (9)

(10)

(11)

(12)

(13)

(14)

(15) (16)

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Figure 1. Developed formulae of the Biclotymol molecule (A) and Haworth projection of chemical structures of α-Pentaacetylglucose (B) and β-Pentaacetylglucose (β-acGLU) (C). 163x115mm (150 x 150 DPI)



Figure 2. X-Ray powder diffraction patterns obtained for α-acGLU (blue line), β-acGLU (red line) and Biclotymol (purple line) (A) before melt-quenching and (B) after melt-quenching. Beam cut-off was located close to 6.5° (2θ). 272x208mm (300 x 300 DPI)


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Figure 3. TM-DSC measurements of crystalline and amorphous forms of Biclotymol (top panel), α-acGLU (left panel) and β-acGLU (right panel). (1) Melting of the commercial stable form, (2) glass transition region, (3) crystallization of the supercooled melt to the crystalline form, (4) melting of the crystalline form. 272x208mm (300 x 300 DPI)



Figure 4. X-ray Powder Diffraction patterns for melt-quenched representative mixtures: (left panel) meltquenched Biclotymol-α-acGLU and (right panel) melt-quenched Biclotymol-β-acGLU. XRPD analysis was performed directly after the production of samples. 272x208mm (300 x 300 DPI)


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Figure 5. TM-DSC thermograms obtained for melt-quenched Biclotymol-α-acGLU (left panel) and meltquenched Biclotymol-β-acGLU (right panel) solid dispersions during heating. 272x208mm (300 x 300 DPI)



Figure 6. X-ray Powder Diffraction patterns for melt-quenched representative mixtures after 4 months of storage at 293 K, 30% RH: (left panel) melt-quenched Biclotymol-α-acGLU and (right panel) melt-quenched Biclotymol-β-acGLU. 272x208mm (300 x 300 DPI)


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Figure 7. Imaginary (ε″) parts of the complex dielectric permittivity vs frequency in the glassy (T < Tg) and supercooled liquid states (T > Tg) for (a) pure α-acGLU, (b) β-acGLU and (c) pure Biclotymol. Left vertical axe corresponds to the imaginary permittivity of the α-process while right vertical axe represents the γprocess. 272x208mm (300 x 300 DPI)



Figure 8. Dielectric loss spectra of representative amorphous solid dispersions between Biclotymol and αacGLU, analyzed above and below Tg. (a) Biclotymol - α-acGLU 1:5 (b) Biclotymol - α-acGLU 1:2 (c) Biclotymol - α-acGLU 1:1 (d) Biclotymol - α-acGLU 2:1 (e) Biclotymol - α-acGLU 5:1. Left vertical axe corresponds to the imaginary permittivity of the α-process while right vertical axe represents the γ-process. 272x208mm (300 x 300 DPI)


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Figure 9. Dielectric loss spectra of representative amorphous solid dispersions between Biclotymol and βacGLU, analyzed above and below Tg. (a) Biclotymol - β-acGLU 1:5 (b) Biclotymol - β-acGLU 1:2 (c) Biclotymol - β-acGLU 1:1 (d) Biclotymol - β-acGLU 2:1 (e) Biclotymol - β-acGLU 5:1. Left vertical axe corresponds to the imaginary permittivity of the α-process while right vertical axe represents the γ-process. 272x208mm (300 x 300 DPI)



Figure 10. Relaxation map of pure Biclotymol, pure α-acGLU, pure β-acGLU and amorphous solid dispersions. Solid gray lines are the VTF fits to the of structural α-relaxation times, illustrated by filled symbols. Temperature dependence of the secondary γ-relaxations is illustrated by open symbols and was fitted by the Arrhenius equation. 288x201mm (300 x 300 DPI)


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Figure 11. Temperature dependence of the dielectric strength for α- relaxation (∆εα) versus temperature for all investigated amorphous solid dispersions. Left panel a) corresponds to Biclotymol-α-acGLU blends while right panel b) matches with Biclotymol-β-acGLU mixtures. 272x208mm (300 x 300 DPI)



Figure 12. Optimized structures of Biclotymol-α-acGLU (upper panel) and Biclotymol-β-acGLU (lower panel) and corresponding complexation energies. 272x208mm (300 x 300 DPI)


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