Investigation into the Solid-State Properties and Dissolution Profile of

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An investigation into the solid-state properties and dissolution profile of spray dried ternary amorphous solid dispersions: A rational step towards the design and development of multi-component amorphous system Shrawan Baghel, Helen Cathcart, and Niall J. O'Reilly Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00306 • Publication Date (Web): 18 Jul 2018 Downloaded from http://pubs.acs.org on July 19, 2018

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Molecular Pharmaceutics

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Title: An investigation into the solid-state properties and dissolution profile of spray

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Shrawan Baghel, Helen Cathcart and Niall J. O’Reilly

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Synthesis and Solid State Pharmaceutical Centre (SSPC), Pharmaceutical and Molecular Biotechnology Research Centre (PMBRC), Waterford Institute of Technology, Cork Road, Waterford, Ireland.

dried ternary amorphous solid dispersions: A rational step towards the design and development of multi-component amorphous system

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1 ACS Paragon Plus Environment

Molecular Pharmaceutics 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

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ABSTRACT:

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The formulation of oral amorphous solid dispersions (ASD) includes the use of excipients to

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improve physical stability and enhance bioavailability. Combinations of excipients (polymers

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and surfactants) are often employed in pharmaceutical products to improve the delivery of

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poorly water-soluble drugs. However, additive interactions in multi-component ASD systems

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have not been extensively studied and may promote crystallization in an unpredictable

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manner, which in turn may affect the physical stability and dissolution profile of the product.

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The main aim of this study was to understand the effect of different surfactant and polymer

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combinations on the solid-state properties and dissolution behaviour of ternary spray dried

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solid dispersions of dipyridamole and cinnarizine. The surfactants chosen for this study were

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sodium dodecyl sulphate and poloxamer 188 and the model polymers used are polyvinyl

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pyrrolidone K30 and hydroxypropyl methylcellulose K100. The spray dried ternary

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dispersions maintained higher supersaturation compared to either the crystalline drug

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equilibrium solubility or their respective physical mixtures. However, rapid and variable

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dissolution behaviour was observed for different formulations. The maximum supersaturation

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level was observed with drug-polymer-polymer ternary dispersions. On the other hand,

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incorporating the surfactant into binary (drug-polymer) and ternary (drug-polymer-polymer)

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ASDs adversely affected the physical stability and dissolution by promoting crystallization.

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Based on these observations, a thorough investigation into the impact of combinations of

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additives on amorphous drug crystallization during dissolution and stability studies is

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recommended in order to develop optimized formulations of supersaturating dosage forms.

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Keywords: Amorphous solid dispersion, spray drying, dissolution, supersaturation, drug-

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polymer interaction, nuclear magnetic resonance, crystallization, surfactant, synergism

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1. INTRODUCTION

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The majority of new chemical entities in the development pipeline are poorly water

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soluble, thereby posing a challenge for oral formulation development.1 Various strategies,

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such as formation of prodrug,2 lipid formulations,3 micronization,4 surfactants,5 salt

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formation,6 and the development of amorphous solid dispersions (ASDs)7 have recently been

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utilized to enhance the solubility and dissolution rate of poorly soluble active pharmaceutical

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ingredients (APIs). Amorphization of crystalline drugs is a promising strategy to overcome

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the solubility challenge.8 Being a thermodynamic high-energy form (random arrays of

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molecules), the apparent solubility and dissolution rate of amorphous APIs are higher than

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their crystalline counterparts.9, 10 However, the high free energy of the amorphous form also

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renders it prone to crystallization and gives rise to physical instability.11 Crystallization of

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APIs is a two-step process involving nucleation followed by crystal growth.11 Nucleation is a

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process in which the drug molecules form small stable clusters or aggregates of a critical size.

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This is a rate limiting step in the crystallization process and the rate of nucleation depends on

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the crystallization activation energy or solid-liquid interfacial energy.12,

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crystal growth phase is governed by the diffusion of solute molecules to the nuclei interface

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and addition to the crystal lattice. Thus, one of the main challenges in formulating ASDs is

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the prevention of nucleation and crystal growth in APIs which results in poor physical

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stability and compromised oral bioavailability.9, 14

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The subsequent

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In an attempt to delay crystallization and improve physical stability, different

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polymers (which interfere with either nucleation or crystal growth or both) have been used to

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prepare binary ASDs.15 Polymers, usually used at high concentrations, reduce the molecular

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mobility of the amorphous API in a binary dispersion by increasing the glass transition

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temperature (Tg) of the system. While it is important to improve the physical stability of ASD

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formulations, generating and maintaining drug supersaturation during dissolution is equally

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important.16 When the intraluminal concentration of an orally administered drug exceeds its

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thermodynamic equilibrium solubility, the drug is supersaturated in the gastric media.

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Recently, binary ASDs (drug-polymer) have gained attention as an effective method of

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improving the supersaturation concentration of poorly soluble drugs during dissolution.17, 18

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Different mechanisms have been proposed to explain the improvement in drug dissolution

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and stability from binary ASDs including the formation of fine particles, drug-polymer

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interaction in solution, formation of a physical barrier to crystallization (adsorption of the



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polymer molecules onto the crystal surfaces), viscosity enhancement, reduction in Gibb’s free

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energy and an anti-plasticization effect of polymer on the drug.9, 19

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Conceptually, multi-component ASDs are considered to be an option to further

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improve the solubility of poorly water-soluble drugs. A multi-component system,

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incorporating other pharmaceutical excipients in addition to the drug and amorphous polymer

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matrix, modifies the drug particles’ microenvironment at the dissolution front leading to the

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enhancement of API solubility.20 The physical stability of the amorphous dispersions can be

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improved by the selection of appropriate matrix components for multi-component system.21

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Therefore, multi-component ternary ASDs composed of API, amorphous polymer matrix and

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functional excipients are considered to be a propitious step towards the improvement of

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physical stability and enhancement of dissolution of poorly water-soluble drugs. However, in

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formulating such systems several issues, such as the formation of homogenous dispersions

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and the physical stability, should be considered. It has been observed that in some cases the

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solution concentration of free drug during the dissolution of ternary ASDs (drug, polymer and

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an additive) declined due to the recrystallization of an amorphized additive.22 It has also been

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reported that multi-component systems of drug and polymer may undergo phase separation

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due to the addition of an additive to the binary ASD system.23 There is a paucity of literature

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on the application of multi-component spray dried solid dispersions and further research is

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required to understand and optimize ternary ASDs. Thus it would seem that the choice and

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quantity of functional additive may be critical to formulating stable, multi-component ASDs.

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Therefore, a rational starting point towards the design of a multi-component ternary ASDs,

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where the API is one of the amorphous state components, would be a ternary mixture of

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amorphous polymer and functional excipients forming drug-polymer-excipient system.

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Generally the third component is either a polymer or surfactant to form ternary ASDs.

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To date, very few studies have examined the effect of a third component on the stability and

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dissolution of ASDs.23, 24, 25, 26 The addition of a third component commonly aims to further

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improve the physical stability and increase the dissolution by inhibiting drug recrystallization

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during shelf life and in solution state, respectively. Moreover, it would be interesting to see

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the effect of combining two different polymers which have different types of interactions

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with the drug on the physical stability and dissolution behaviour of ternary ASDs. Although

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there are many publications on amorphous drug crystallization inhibition in the presence of a

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single polymer (binary ASDs), there is a need to understand drug crystallization (both in the

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solid-state and during dissolution) in the presence of two polymers (ternary ASDs). Due to an 4 ACS Paragon Plus Environment

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increase in the overall number of poorly soluble APIs, ternary ASDs having two different

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polymers may be utilised to further enhance their physical stability and apparent solubility.

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Another class of pharmaceutical excipient used to improve the aqueous solubility and

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dissolution performance of poorly water-soluble drugs are surfactants.27, 28 As a consequence,

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it may be expected that incorporating surfactants into ASDs to form drug-polymer-surfactant

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ternary ASDs may further enhance the dissolution rate of the poorly water-soluble drug by

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promoting wettability of the particles. In this work, the main reason for choosing surfactants

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as third component in addition to binary drug-polymer combinations was based on the fact

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that polymer may dissolve the amorphous drug in the solid state, leading to a stable system

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without crystallization or phase separation, while the surfactant may promote wettability in

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solution which can lead to an increase in solubility and dissolution rate of the drug.

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Previously, surfactants have been used as plasticizers for polymers during hot melt extrusion

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processes to enhance drug-polymer miscibility.29, 30 However, currently there is very limited

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literature available on the preparation and characterization of spray dried drug-polymer-

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surfactant dispersions and therefore, it is of interest to study the effect of surfactants on ASD

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properties when incorporated within spray dried ASDs.31,

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surfactants on drug release from ASDs has also been reviewed, with some studies finding a

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positive impact on the release kinetics of hydrophobic APIs and others reporting a negative

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effect of surfactants on the dissolution of amorphous drugs from solid dispersions.33, 34 It is

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therefore reasonable to suggest that surfactants, like polymers, may have an impact on the

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physical stability and dissolution behaviour of ASDs and it is of interest to explore this

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possibility. Consequently, the physical stability and dissolution behaviour of spray dried

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ASDs with and without surfactants as a ternary agent will also be investigated in this study.

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Furthermore, the role of

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We have chosen polyvinyl pyrrolidone K30 (PVP), hydroxypropyl methylcellulose

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K100 (HPMC) and a combination of both as a carrier matrix for ASDs. The surfactants

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selected for this study are poloxamer 188 (P188) and sodium dodecyl sulphate (SDS). P188,

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which is a non-ionic, triblock copolymer, comprised of a hydrophobic block of polypropylene

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glycol and two hydrophilic blocks of polyethylene glycol, is categorised as a surfactant in this

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study as the use of this excipient in the pharmaceutical area is related to its surfactant

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properties. The other surfactant investigated in this study is SDS, which is an anionic

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surfactant. The selection of these excipients was based on the anticipation that differences in

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their physicochemical characteristics may allow one to distinguish the critical factors

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affecting the drug-polymer interactions and miscibility more clearly. As a control, we have 5 ACS Paragon Plus Environment


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also studied the drug-polymer-polymer-surfactant (quaternary ASDs) combinations to probe

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the effect of surfactant on drug-polymer-polymer system.

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Dipyridamole (DPM) and cinnarizine (CNZ) were selected as model drugs because of

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their poorly water-soluble properties. Although weakly basic and therefore soluble in gastric

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media in the crystalline state, DPM and CNZ have been chosen as model compounds for

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amorphous solid dispersion studies to understand the mechanism involved in improving

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physical stability and aqueous solubility. They are particularly suited because:

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1. They are typical BCS class II drugs with practical poor aqueous solubility (~6.8

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µg/mL at pH 6.8 for DPM and ~2 µg/mL at pH 6.5 for CNZ) and high GI membrane

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permeability (Log P values for DPM and CNZ are 3.71 and 5.71, respectively).11, 19

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2. The glass transition temperatures of DPM and CNZ are ~38°C and ~6°C,

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respectively.11 It would be interesting to see the behaviour of two different compound, one

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having Tg above room temperature (DPM) and the other having Tg below room temperature

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(CNZ).

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3. DPM and CNZ have a different number of H-bond donor (DPM – 4 and CNZ – 0)

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and acceptor groups (DPM – 12 and CNZ – 2).19 Thus, it would be interesting to compare the

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recrystallization tendency of DPM and CNZ in a polymer matrix since both the drugs have

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different nature and strength of forming H-bonds.

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Recently, we have reported that the DPM and CNZ are very unstable in their

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amorphous forms and have high crystallization tendency.11 We also reported the role of drug-

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polymer interaction and anti-plasticization in improving the solid-state stability and in-vitro

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dissolution of DPM and CNZ binary ASDs.19 14 This is a continuation of our previous work

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in order to understand the role of polymer-surfactant and polymer-polymer combinations on

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the physical stability and dissolution profile of ASDs by preparing and characterizing spray

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dried binary (drug-polymer), ternary (drug-polymer-surfactant or drug-polymer-polymer) and

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quaternary

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characterized by differential scanning calorimetry (DSC), modulated DSC, Fourier-transform

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infrared (FTIR), in-vitro dissolution, 1H nuclear magnetic resonance (NMR) and dynamic

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vapour sorption (DVS). This study will add to the overall understanding of the use of

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excipients in ASDs and will help in future multi-component amorphous product

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development.

(drug-polymer-polymer-surfactant)

solid

dispersions.


The

ASDs

were

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2. MATERIALS AND METHODS

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2.1. Materials

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Dipyridamole (DPM), cinnarizine (CNZ), polyvinyl pyrrolidone K30 (PVP) and

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poloxamer 188 were supplied by Sigma Aldrich, Ireland. Hydroxypropyl methylcellulose

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K100 (HPMC) was obtained from Colorcon, England, and sodium dodecyl sulphate (SDS)

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(>99%) was obtained from Fisher Scientific, U.K. All reagents were of analytical grade and

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used without further purification. The chemical structure and key physicochemical properties

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of the model drugs and polymers used in this study are shown in Figure 1 and Table 1,

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respectively.

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Table 1. Physicochemical properties of model drugs and polymers

Log P b

pKa

37.44

3.71

6.435

121.25

5.86

5.71

8.436

-

-

164.13

-

-

450,000

-

-

153.83

-

-

SDS

288.37

-

-

-

-

-

P188

102.13

14.43

48.67

-

-

-

Molecular

ᅪࡴࢌ

ࢀ࢓

ࢀࢍ

weight (g/mol)

(kJ/mol)a

(°C)a

(°C)a

DPM

504.63

29.06

168.11

CNZ

368.51

38.33

PVP

40,000

HPMC

200

a

b

201

2.2. Preparation of amorphous solid dispersions

Values obtained from DSC (n=3), Values obtained from literature

19

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The spray dried solid dispersions were prepared using a Pro-C-epT 4M8-TriX spray

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drier (Zelzate, Belgium) with a bifluid nozzle. The spray drying solutions were prepared by

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dissolving the component mixtures in dichloromethane-ethanol mixture (50:50 v/v). The

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drug-polymer proportion in the binary mixture was 20:80 w/w. For the ternary solid

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dispersion systems, the proportion of drug-polymer-surfactant was 20:75:5 and drug-

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polymer-polymer was 20:40:40. The amount of surfactant in ternary ASDs was kept low as

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they are not well tolerated in the body at high concentration.9 The proportion of drug-

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polymer-polymer-surfactant in quaternary systems was 20:37.5:37.5:5 w/w. The key

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processing parameters were feed concentration (10% w/v in dichloromethane-ethanol

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mixture), spray rate (6 mL/min), nozzle size (0.2 mm), atomization air flow rate (5 L/min),

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inlet temperature (80 ± 5°C), outlet drying temperature (50 ± 5°C) and drying air rate (100

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± 10 L/min). The spray dried solid dispersions were collected using a small cyclone separator

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and stored in a vacuum desiccator at room temperature for further analysis. The powder yield

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obtained was approximately 60-70% w/w. 7 ACS Paragon Plus Environment


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2.3. Preparation of physical mixtures

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Physical mixtures for in-vitro dissolution testing and melting point depression (MPD)

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analysis were prepared by manually mixing the components by mortar and pestle. The weight

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fraction of drug, polymer and surfactant for in-vitro dissolution testing was identical to the

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weight fraction used for preparing the spray dried solid dispersion. The ratio of drug and

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polymer chosen to perform MPD analysis for binary systems was 95:5, 90:10, 85:15 and

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80:20 w/w and for ternary systems (dug-polymer-polymer) was 95:2.5:2.5, 90:5:5, 85:7.5:7.5

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and 80:10:10 w/w.

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2.4. Thermogravimetric analysis (TGA)

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The residual solvent content of the spray dried solid dispersions was assessed using a

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TGA Q50 (TA Instruments Corp., Elstree, Herts, U.K.). Samples were heated at 10°C/min

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from 25 to 200 °C. During all TGA experiments nitrogen was used as the purging gas at 50

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mL/min. All analyses were performed in duplicate.

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2.5. Differential scanning calorimetry (DSC)

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Thermal behaviour of the ASDs was analysed using a TA instrument Q2000 DSC.

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Temperature and heat flow calibration was carried out using a high-purity indium standard.

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Nitrogen was used as the purge gas at a flow rate of 50 mL/min. 3-5 mg of samples were

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accurately weighed into aluminium pans with pin holes. The samples were heated from 0 to

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200 ºC at a heating rate of 10 ºC/min. MPD analysis was carried out at a heating rate of 2

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ºC/min from 0 to 200 ºC. The glass transition temperature (Tg) of the freshly prepared and

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aged samples was analysed using modulated DSC (mDSC). 3-5 mg of the samples were

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accurately weighed into aluminium pans with pin holes. The experiment was performed

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under nitrogen gas flow (50 mL/min) using an underlying heating rate of 5 ºC/min from 0 to

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200 ºC and a modulation amplitude of ± 0.53 ºC over a period of 40 s for all the samples. All

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measurements were performed in triplicate and data analysis was performed using Universal

241

Analysis Software (TA instruments).

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2.6. Fourier-Transform Infrared Spectroscopy

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Fourier-transform Infrared Spectroscopy (FTIR) was performed using a Varian 660-

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IR FT-IR Spectrometer (32 scans at 4 cm-1 resolution). Test samples were mixed with KBr

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and then compressed into a disk and analysed immediately.


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2.7. In-vitro dissolution study of solid dispersions

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The equilibrium solubility of crystalline drugs and dissolution rate of amorphous

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DPM and CNZ from various powdered physical mixtures and ASDs, respectively, were

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measured using the USP II paddle method. Samples containing 25 mg of DPM and CNZ

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were added to 500 mL of phosphate buffer solution pH 6.8 (PBS 6.8) at 37.0 ± 0.2 °C. The

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solution was stirred at 100 rpm using a USP II paddle apparatus. 2 mL samples were

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withdrawn from each vessel at pre-defined intervals (5, 10, 15, 30, 60, 120, 180, 240, 300,

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360 and 1440 min) and centrifuged for 5 min at 15000 rpm. At each time-point the same

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volume of fresh medium was replaced. The concentration of DPM and CNZ was determined

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using a UV-Vis spectrophotometer (Varian VK 7010 L1168, Santa Clara, USA). All

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measurements were carried out in duplicate.

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2.8. Solution state Nuclear Magnetic Resonance (NMR)

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In order to understand the molecular mechanism of drug-polymer and drug-polymer-

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polymer interactions, 1H NMR spectra were recorded on a Jeol ECX-400 spectrometer

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operating at 400 MHz. The measurements were performed at 40°C in dimethylsulfoxide

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(DMSO-d6) using tetramethylsilane (TMS) as an internal standard. Initial trials were

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performed using D2O. However the poor solubility of the model drugs in D2O leads to weak

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signals and the chemical shifts were not clear. Therefore, DMSO-d6 has been selected due to

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its high dielectric constant and hydrophilic nature. All the model drugs and polymers were

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completely soluble in DMSO-d6. Furthermore, the molecular interaction between polymer

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and surfactant were characterised by two-dimensional Nuclear Overhauser Effect

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spectroscopy (2D-NOESY) in DMSO-d6. The polymer to surfactant ratio was kept the same

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as that of the dissolution studies. For 2D-NOESY, the mixing time was set to 0.5 s and the

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experiment was performed with a 1.5 s relaxation delay and 0.32 s acquisition time.

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2.9. Moisture sorption analysis and Stability studies

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Moisture sorption analysis of the ASDs was carried out using dynamic vapour

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sorption (DVS)-1000 Intrinsic, Surface Measurement Systems, U.K. Amorphous drug

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samples (5-10 mg) were analysed using a double ramp method from 0-90-0% RH (2 cycles)

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in 10% increments (dm/dt = 0.001 at each step) at 40 °C. Solid dispersions were also stored at

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40 °C/75% RH. The physical stability of all the samples was evaluated after 4 weeks.



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3. RESULTS AND DISCUSSION

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The association of polymer-polymer or polymer-surfactant combinations in aqueous

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solution have attracted considerable fundamental and technological interest. The resultant

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properties of these combinations possess unique properties that are significantly different

280

from those of the individual components. Consequently, they have important applications in

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biological and industrial processes.37 For example, synthetic water soluble polymer-polymer

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combinations have been used in operations such as flocculation during mineral processing,38

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while polymer-surfactant combinations have been used for immobilization of enzymes in

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polyelectrolyte complexes,39 rheology control,40 improving the solubility of drugs with low

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aqueous solubility and to control the drug release rate.13

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polymer-surfactant combinations are highly relevant, since pharmaceutical formulations often

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contains both excipients types.25 41 42 Formulations containing high-energy amorphous drugs

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can enhance drug dissolution by generating supersaturated solutions.9 Polymers are

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frequently added to delay crystallization, and surfactants are typically employed to improve

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processing properties or dissolution profiles.14

25 41

Thus, polymer-polymer or

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In the past, several publications have investigated the association between polymer-

292

polymer and polymer-surfactant mixtures in solution.13 25 41 42 The presence of hydrophilic

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excipients, such as polymer or surfactant, in a formulation containing a polymeric matrix may

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help prevent amorphous drug crystallization and/or prevent agglomeration of a fine

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crystalline precipitate into larger aggregates.9 However, there has been limited systematic

296

investigation of the interplay between surfactant or polymeric additive combinations in terms

297

of the impact on solid-state properties and dissolution behaviour, although such an interplay

298

could be very influential on the performance of the dosage form. Excipients such as polymers

299

or surfactants are well-known to impact nucleation and crystal growth and may accelerate or

300

inhibit crystallization depending on their effect on crystallizing solute and solution

301

properties.41 42 This is important in the context of formulation of dosage forms where the goal

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is to prevent crystallization of amorphous drug during the shelf-life or dissolution. It is thus

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crucial to probe into the effect of excipient combinations on the solid-state properties and

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dissolution profile of amorphous drugs within solid dispersions, since the interaction can

305

result in change in dispersion properties which may result in favourable or adverse effect on

306

the amorphous drug crystallization inhibition. In this study, we have investigated the effect of

307

polymer-polymer and polymer-surfactant combinations on the physical stability and

308

supersaturation behaviour during dissolution of poorly water-soluble model drugs. 10 ACS Paragon Plus Environment

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3.1. Drug-polymer and drug-polymer-polymer miscibility

310

The first step towards developing a multi-component amorphous systems is to assess

311

the miscibility of the drug within the polymer matrix. Drug-polymer miscibility is crucial

312

requirement for the formulation of stable ASDs.19 Solubility parameters (δ) are used widely

313

to quickly and effectively determine the drug-polymer miscibility when screening different

314

systems.43 Previously, we reported the δ values of DPM (28.57 MPa1/2), CNZ (21.00 MPa1/2)

315

and PVP (26.28 MPa1/2).19 The δ value of HPMC, calculated in this study, is 22.48 MPa1/2. It

316

has been reported that compounds with a ∆δ of less than 7.0 MPa1/2 are likely to be miscible

317

because the energy released by the interaction between the components balances the enthalpy

318

of mixing within the components.25 On the other hand, compounds with ∆δ greater than 10.0

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MPa1/2 are likely to be immiscible. In this study, both the model polymers (PVP and HPMC)

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were expected to be miscible with both drugs (DPM and CNZ), as they exhibited a ∆δ of less

321

than 7.0 MPa1/2.

322

To further investigate the drug-polymer and drug-polymer-polymer interaction and

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the likelihood of the formation of a miscible system after spray drying, we employed melting

324

point depression (MPD) analysis. The chemical potential of a crystalline material becomes

325

equal to the chemical potential of its molten material at its melting point. However, drug-

326

polymer miscibility reduces the chemical potential of the drug in the solution (molten drug

327

and polymer mixture), compared to the pure molten drug, which leads to a depression in

328

melting point of the drug dissolved in the polymer.44 Strong exothermic mixing of the drug

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and polymer produces a large depression in melting point of the drug, whereas weakly

330

exothermic mixing or immiscible drug-polymer system should result in less significant MPD

331

or no depression at all. We have employed this method previously to investigate drug-

332

polymer mixing thermodynamics of DPM-PVP and CNZ-PVP systems, which showed clear

333

evidence of a depression of the melting point of both drugs, indicating a significant degree of

334

drug-polymer mixing at the melting temperature of the drug.19 In this work, we have

335

investigated the DSC thermogram for physical mixtures of DPM and CNZ at different weight

336

ratios with HPMC and PVP-HPMC combinations. As shown in Figure 2 and 3, significant

337

mixing of model drugs with HPMC and PVP-HPMC were observed. To compare the

338

depression in melting point due to the individual polymers and their combination, theoretical

339

depression values for the ternary mixtures were proposed based on the contribution of each

340

polymer within the binary systems. Since the ternary mixture contains two polymers (each

341

polymer in half proportion compared to binary system), the depression from both the 11 ACS Paragon Plus Environment


342

polymers was averaged. If the experimental values showed a greater effect compared to this

343

average value, then that would indicate a synergistic benefit. It was found that the depression

344

in melting point of DPM and CNZ in the ternary systems (drug-PVP-HPMC) was higher than

345

the average values from the binary PVP and HPMC systems suggesting synergism (Figure 3).

346

This suggests that ternary ASDs may perform better than binary ASDs in increasing physical

347

stability of amorphous drug within dispersions.

348

3.2. Solid State Characterization of freshly prepared Spray Dried dispersions

349

The spray dried binary, ternary and quaternary solid dispersions were prepared and

350

examined using DSC and MDSC to determine extent of amorphization and glass transition.

351

The spray dried samples were stored in the vacuum desiccator for 48 hrs to remove the

352

residual solvent. In a standard TGA ramp test, all the dispersions showed a residual solvent

353

content of ≤2% w/w.

354 355

3.2.1. Thermal analysis: PVP-based system: As reported in Table 2, all PVP based dispersions were found to

356

be completely amorphous except for the CNZ-PVP-P188 system, where a crystalline CNZ

357

melting peak was observed (see supplementary information for full DSC thermograms). As

358

shown in Figure 4, the DPM-PVP and CNZ-PVP dispersions displayed the highest Tg values

359

(single Tg indicating molecular level mixing of the drug and polymer) when compared to

360

other PVP-surfactant based dispersions (Table 2). The surfactant based PVP dispersions of

361

DPM and CNZ (Figure 4) displayed two Tg’s (DPM-PVP-SDS, DPM-PVP-P188 and CNZ-

362

PVP-SDS) or one Tg along with a melting peak (CNZ-PVP-P188). The ASDs displaying two

363

Tg’s represent amorphous system with phase separation leading to the formation of drug-rich

364

(lower Tg region) and polymer-rich domains (higher Tg region). These results suggest that

365

surfactants have a negative effect on the stability of PVP based DPM and CNZ spray dried

366

ASDs.

367

HPMC-based system: Binary ASDs of DPM and CNZ with HPMC remained

368

completely amorphous as reported in Table 2 (see supplementary information for full DSC

369

thermograms). The dispersions displayed a single Tg (Figure 5) indicating complete mixing

370

and amorphization of the drug with HPMC. The Tg of the DPM-HPMC and CNZ-HPMC

371

systems is higher than the Tg of their PVP counterparts, suggesting that HPMC has a greater

372

antiplactization effect on the model drugs (Figure 5 and Table 2). On the other hand,

373

surfactants were found to have a negative effect on the stability of DPM-HPMC ASDs with a

374

drug melting peak, indicating the presence of crystalline drug. The negative effects of SDS 12 ACS Paragon Plus Environment

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375

and P188 were more pronounced in CNZ-HPMC based dispersions where a CNZ

376

recrystallization peak was also present in addition to drug melting peak. These results

377

indicate that, in the absence of surfactants, HPMC is a better antiplasticizing agent for DPM

378

and CNZ dispersions compared to PVP whereas in the presence of surfactants PVP is a more

379

effective stabilizer of amorphous DPM and CNZ. The presence of SDS and P188 in HPMC

380

based dispersions of DPM or CNZ increased the molecular mobility of the amorphous drugs

381

(lower Tg values compared to drug-polymer system without surfactant) leading to phase

382

separation in DPM dispersions and crystallization in CNZ systems. Surfactants interfered

383

more with the stabilizing efficiency (drug-polymer interaction and miscibility) of HPMC

384

compared to PVP.

385

Table 2: Physicochemical properties of binary, ternary and quaternary ASDs

Formulations

Fresh (n = 3)

Solubility after 24 hr

Aged (n = 3)

(µg/mL) (n = 2)

Tg (°C)

∆Hm (J/g)

Tg (°C)

∆Hm (J/g)

PM

SD

DPM-PVP

147.9

-

138.7/55.3

-

7.04

22.32

DPM-PVP-SDS

139.3/100.2

-

125.8/48.2

-

7.19

19.18

DPM-PVP-P188

145.9/99.2

-

137.6/98.6

-

6.04

17.18

CNZ-PVP

106.5

-

50.8

10.84

2.43

12.84

CNZ-PVP-SDS

100.1/148.2

-

52.1

12.29

2.51

12.20

CNZ-PVP-P188

100.2

2.84

21.7

11.02

2.89

12.53

DPM-HPMC

150.2

-

134.4

1.75

6.93

26.45

DPM-HPMC-SDS

99.9

0.29

98.8

6.95

6.31

18.94

DPM-HPMC-P188

99.3

2.54

98.3

3.43

6.04

21.12

CNZ-HPMC

145.6

-

64.2

2.49

2.38

13.24

CNZ-HPMC-SDS

65.7

6.45

98.4

9.35

2.34

13.23

CNZ-HPMC-P188

41.09

8.53

111.9

10.62

2.09

13.12

DPM-PVP-HPMC

157.7

-

148.6

-

6.66

29.76

DPM-PVP-HPMC-SDS

124.2

-

109.5

-

6.41

25.48

DPM-PVP-HPMC-P188

139.1

-

117.8

-

6.95

21.41

CNZ-PVP-HPMC

66.1/143.5

-

88.2

-

2.11

16.79

CNZ-PVP-HPMC-SDS

9.7

5.78

82.2

16.96

2.27

14.57

CNZ-PVP-HPMC-P188

10.9

5.27

67.9

16.34

2.09

13.49

386 387

PM and SD represents physical mixtures containing crystalline drug and solid dispersions containing amorphous drug, respectively;

388

PVP-HPMC based system: The mDSC thermogram of all the PVP-HPMC based

389

systems are shown in Figure 6 and the Tg values are reported in Table 2. DPM-PVP-HPMC

390

ternary dispersions were found to be amorphous with the Tg of the system significantly higher 13 ACS Paragon Plus Environment


391

than the Tg of the binary DPM-PVP or DPM-HPMC based systems (see supplementary

392

information for full DSC thermograms). This confirms the improved efficiency of the

393

polymer combination in the formation of stable ternary DPM ASDs compared with binary

394

dispersions. Adding surfactants to DPM-PVP-HPMC significantly reduced the Tg of the

395

system. CNZ-PVP-HPMC dispersions displayed two Tg’s suggesting the presence of two

396

different amorphous domains. We have previously reported that CNZ exhibits no interaction

397

with PVP and formed a solid solution with PVP such that the amorphous CNZ was

398

kinetically frozen within the PVP matrix rather than being in a thermodynamic equilibrium.19

399

We found that if the concentration of CNZ within PVP is increased then it will lead to self-

400

association of CNZ molecules leading to phase separation and crystallization. Furthermore,

401

as reported previously (section 3.1 (Figure 2) and section 3.2 (HPMC based systems)),

402

HPMC has a greater stabilizing effect on amorphous CNZ due to strong drug-polymer

403

interaction compared to PVP. Therefore, it could be generalised that the lower concentration

404

of HPMC (40% w/w) in the CNZ ternary dispersion has led to the instability of the system.

405

The two Tg’s of in the CNZ-PVP-HPMC system is in accordance with these observations.

406

Furthermore, the inclusion of surfactant has negatively affected the stability of CNZ-PVP-

407

HPMC system.

408

Based on the DSC results of freshly spray dried ASDs of DPM and CNZ, it was found

409

that the surfactants promote the phase separation and crystallization of amorphous drugs

410

within spray dried ASDs which may be due to the interference with the drug-polymer

411

interaction or miscibility. In addition, the synergistic effect of PVP-HPMC combinations was

412

observed to be stronger in the DPM dispersions than CNZ dispersions.

413 414

3.2.2. Spectroscopic Analysis FTIR spectroscopy was used to assess the molecular interactions within the samples.

415

The FTIR spectra of DPM, CNZ, PVP, HPMC and their solid dispersions are shown in

416

Figure 7. The characteristic peaks of DPM are present at 1359 cm-1 (C – N bonds), 1533 cm-1

417

(C = N ring), 2851 cm-1 (symmetrical stretching of CH2 group), 2923 cm-1 (asymmetrical

418

stretching of CH2 group) and 3303/3377 cm-1 (OH stretching vibration). The CNZ spectra

419

displayed characteristic peaks at 963 cm-1 (aromatic out-of-plane), 1001 cm-1 (= C – H

420

alkene), 1141 cm-1 (C – N stretching peak), 2956 cm-1 (aliphatic CH stretching peak), 3021

421

cm-1 (alkene CH stretching) and 3066 cm-1 (aromatic CH stretching). The spectra of the

422

physical mixtures of DPM and CNZ with PVP, HPMC and surfactants are not shown here as

423

they did not show any apparent changes in the FTIR spectra. 14 ACS Paragon Plus Environment

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424

The formation of DPM ASD with PVP, HPMC and PVP-HPMC resulted in the

425

disappearance of DPM OH stretching vibration indicating the formation of hydrogen bonds

426

with the polymers (Figure 7). Broadening (DPM-PVP, DPM-HPMC and DPM-PVP-HPMC)

427

and shifting (DPM-PVP-HPMC) of symmetrical (2851 cm-1) and asymmetrical (2923 cm-1)

428

stretching of DPM CH2 group was also observed suggesting drug-polymer-polymer

429

interaction was stronger compared to drug-polymer interaction. Shifts were also recorded for

430

C = N and C-N bands at 1533 and 1359 cm-1 in DPM-PVP-HPMC system. CNZ, on the other

431

hand, displayed no interaction with PVP but HPMC based CNZ dispersions demonstrated the

432

presence of drug-polymer interaction (shifts in CNZ C – N peak). These shifts and

433

broadening of peaks were observed in CNZ-PVP-HPMC dispersion which could be due to

434

the synergistic interaction between CNZ and PVP-HPMC combination. This helps explain

435

the better synergistic effect of PVP-HPMC on DPM compared to CNZ; both the PVP and the

436

HPMC interact with DPM individually whereas only the HPMC interacts with the CNZ. This

437

highlights the importance of the nature and strength of drug-polymer interactions while

438

choosing a polymer combination for stabilizing amorphous drug. Furthermore, on comparing

439

drug-PVP-HPMC spectra of DPM and CNZ with drug-PVP-HPMC-SDS displayed

440

significant differences with reference to peak broadening and shifts suggesting the presence

441

of surfactant affects drug-polymer-polymer interactions (Figure 7). It is important to mention

442

here that FTIR spectroscopic studies conducted here are only for qualitative purpose and do

443

not provide any quantitative understanding of the molecular interactions. Nevertheless, when

444

combined with the DSC results, they help build a better understanding of molecular

445

interactions.

446

3.3. Supersaturation generation and maintenance

447 448

3.3.1. Equilibrium solubility The effect of various compositions of physical mixtures (containing crystalline drug)

449

and solid dispersions (containing amorphous drug) on the equilibrium solubility of DPM and

450

CNZ in PBS 6.8 are reported in Table 2. For direct comparison, the composition of physical

451

mixtures has been kept the same as that of respective solid dispersion. The physical mixtures

452

of DPM and CNZ with polymers and/or surfactants did not result in a significant change in

453

the equilibrium solubility of crystalline DPM and CNZ. The reported CMC of poloxamer

454

188 and SDS are 0.743 mg/mL and 0.29 mg/mL.45 46 The presence of surfactants (P188 and

455

SDS) in physical mixtures with concentration below their respective critical micelle

456

concentration (CMC) in PBS 6.8 did not result in any significant rise in the solubility of 15 ACS Paragon Plus Environment


Page 16 of 45

457

crystalline DPM and CNZ. Moreover, PVP, HPMC and their combination also have no effect

458

on the equilibrium solubility of the crystalline DPM and CNZ (Table 2). On the other hand,

459

the equilibrium solubility of amorphous drugs in the solid dispersions after 24 hr was much

460

higher than their physical mixture (crystalline drug) counterparts. Thus, the higher drug

461

concentration during dissolution was not due to the solubilising effect of polymers and

462

surfactant on the crystalline drug. It is due to crystallization inhibition efficiency of the

463

polymer in solution to maintain apparent higher solubility of amorphous drug. Furthermore,

464

the maintenance of amorphous DPM and CNZ supersaturation in PBS 6.8 was due to the

465

polymers rather than the surfactants. This was confirmed when the amorphous drug

466

equilibrium solubility from surfactant based ASDs (higher amorphous drug solubility) was

467

compared to their surfactant free counterpart (lower amorphous drug solubility).

468

maximum supersaturation concentration of DPM and CNZ was observed in drug-polymer-

469

polymer combinations which again suggests a synergistic effect of this polymer-combination

470

on drug supersaturation. By comparison, surfactants were found to have negative impact on

471

the amorphous drug supersaturation maintenance (Table 2) with lower concentrations

472

observed after 24 hrs for ASDs containing surfactants. The difference in drug concentration

473

was found to be significant for drug-polymer or drug-polymer-polymer systems compared to

474

surfactant incorporated dispersions.

475 476

3.3.2. In-vitro dissolution studies To further understand how the molecular interactions in the multi-component solid

477

dispersions affect the DPM and CNZ release profile from spray dried ASDs in pH 6.8 buffer,

478

in-vitro dissolution experiments were performed. Of particular interest was whether the

479

synergistic effect of the polymer combinations and the incorporation of surfactants into the

480

solid dispersions affected the generation and maintenance of DPM and CNZ supersaturation.

481

It is important to note that pH 6.8 buffer was chosen only to understand the effects of

482

excipients (drug-excipient interactions, antiplasticization etc.) on the apparent solubility of

483

amorphous drugs from solid dispersions. In order to isolate these effects we have chosen

484

simple discriminatory media. More complex simulated body fluids also contain surfactants

485

and other components which may directly affect the dissolution behaviour of the

486

formulations. Further experimental work would be required to study this in detail which is

487

outside the scope of this article.

The

488

The dissolution profile of spray dried dispersions of DPM in PBS 6.8 (Figure 8)

489

demonstrated that supersaturation was generated rapidly with a maximum concentration 16 ACS Paragon Plus Environment

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490

(Cmax) achieved within 5 min. Then, a rapid drop in the free DPM concentration was

491

observed, suggesting that water-mediated crystallization predominated in this stage. Once the

492

concentration of DPM reached a plateau, the dissolution process was in equilibrium with the

493

crystallization process. Significant differences were found between the Cmax for different

494

systems (PVP, HPMC and PVP-HPMC based dispersions). The descending order of Cmax is

495

DPM-PVP-HPMC > DPM-PVP > DPM-HPMC.

496

combination has a synergistic effect on generating and maintaining DPM supersaturation.

497

The presence of 5% w/w SDS or P188 in the formulations have variable effects on the

498

dissolution profile of DPM. SDS or P188 had a minimal effect on the dissolution profile of

499

DPM in PVP based dispersions (Figure 8 (a)). This suggests that the surfactants did not have

500

any significant influence on the DPM dissolution profile in PVP based dispersions. In DPM-

501

HPMC systems, both SDS and P188 had a significant effect on the supersaturation level of

502

DPM (Figure 8 (b)), adversely affecting the release of DPM as indicated by the lower Cmax

503

attained in the presence of SDS or P188. The level of supersaturation achieved and the

504

duration of supersaturation maintained was found to be maximum for DPM-HPMC system

505

followed by DPM-HPMC-P188 dispersion and the lowest for DPM-HPMC-SDS system.

506

These results suggest that the presence of the surfactant did not inhibit DPM crystallization

507

during dissolution to the same extent as their surfactant free counterparts in the HPMC-based

508

dispersions. Similar results have been observed for DPM-PVP-HPMC based systems (Figure

509

8 (c)) where the dissolution profile of the DPM dispersions without SDS or P188 was

510

significantly better than the dispersions with surfactants. The decreasing order of dissolution

511

performance is as follows: DPM-PVP-HPMC > DPM-PVP-HPMC-P188 > DPM-PVP-

512

HPMC-SDS.

Thus, it was found that PVP-HPMC

513

The effect of binary, ternary and quaternary combinations of drug, polymer and

514

surfactant on the dissolution profile of spray dried CNZ dispersions was also investigated.

515

The dissolution profiles of CNZ solid dispersions in PBS 6.8 containing a combination of

516

polymer and surfactants are illustrated in Figure 9. CNZ, in PVP and PVP-HPMC based

517

formulations, achieved a Cmax within 5 min followed by a decline in free CNZ concentration,

518

indicating that CNZ crystallizes quickly in the presence of water. This could be due to strong

519

plasticization effect of water on the amorphous drug. The CNZ-HPMC system, on the other

520

hand, achieved a maximum concentration after 120 mins followed by decline in free drug

521

concentration. The dissolution of ternary CNZ-PVP-HPMC resulted in significantly higher



522

CNZ concentration in solution compared to CNZ-PVP and CNZ-HPMC binary dispersions.

523

The effect of surfactants on CNZ dissolution is similar to that of DPM dispersions.

524

The dissolution results suggests that the surfactants interfere with the crystallization

525

inhibitory efficiency of the polymers. The effect of SDS and P188 on HPMC based

526

dispersions of DPM and CNZ is more pronounced than in the PVP based systems. The effect

527

is even more pronounced in PVP-HPMC based dispersions of DPM and CNZ. There are two

528

possible explanations for the lower drug supersaturation in the presence of surfactants. The

529

first possibility is that the surfactant and polymer molecules could be competing to interact

530

with the drug molecules.41 Due to the hydrophobic nature of DPM and CNZ, there was a

531

higher tendency for the hydrophobic parts of SDS and P188 molecules to interact to DPM or

532

CNZ molecules than for the hydrophilic HPMC or PVP-HPMC polymers. The adsorption of

533

surfactant molecules on to the drug molecules would lead to a reduced interfacial tension

534

which eventually reduces the nucleation activation energy, finally leading to a higher

535

nucleation rate. 9, 20, 41 Another possible explanation for the reduced supersaturation level is

536

that the polymer and surfactant molecules interact to form clusters and therefore the number

537

of freely available polymer molecules to inhibit the crystallization of dissolved DPM and

538

CNZ molecules is reduced.47,

539

performance of spray dried solid dispersion formulations may be counterproductive.

540 541

3.3.3. Solution 1H NMR studies Solution 1H NMR spectroscopic studies were performed to probe the molecular

542

mechanism behind the improved supersaturation performance of ternary drug-polymer-

543

polymer ASDs of DPM and CNZ. This study was performed on the best performing ASDs

544

(generating and maintaining highest level of supersaturation) screened during the dissolution

545

studies and compared to the binary drug-polymer ASDs. This study was performed to study

546

the site of interaction between the drug and polymer in solution to help explain the results

547

obtained in the dissolution studies. The peak shifts in 1H NMR spectra of DPM, CNZ and

548

their binary and ternary ASDs (without surfactants) are shown in Figure 10 and 11. The full

549

NMR spectra of drug, polymer and their solid dispersions are provided in supplementary

550

information.

48

Thus, the use of surfactant to enhance the dissolution

551

As shown in Figure 10, the chemical shift of protons (1) and (3) shifted downfield to

552

higher values in all the systems. This suggests the deshielding of the protons in the presence

553

of polymers. A chemical shift for proton (2) and (4) was not observed in DPM-PVP system

554

whereas a deshielding effect was observed in the DPM-HPMC and DPM-PVP-HPMC 18 ACS Paragon Plus Environment

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555

systems. In case of CNZ, the shifts were most pronounced for protons (1), (2), (6) and (7) of

556

CNZ in PVP dispersions and for protons (1), (2), (3), (4), (5), (6) and (7) in HPMC and PVP-

557

HPMC systems (Figure 11). The shifts shown in Figure 10 and 11 suggests DPM and CNZ

558

interact with PVP, HPMC and PVP-HPMC systems in a different way which goes some way

559

towards explaining the different polymeric effect, particularly in terms of inhibition of drug

560

recrystallization during dissolution of DPM and CNZ ASDS. The larger peak shifts

561

corresponds to the possibility of stronger drug-polymer interaction in ternary system

562

compared to individual PVP and HPMC binary systems. The significantly higher shifts in

563

ternary systems again suggests a synergistic effect of polymer on the drug-polymer

564

interaction in solution. The relative extent of shift, in the decreasing order, was drug-PVP-

565

HPMC > drug-HPMC > drug-PVP (for both the drugs) which explains the dissolution results

566

where the ternary drug-PVP-HPMC generated and maintained highest level of

567

supersaturation compared to other systems studied. This also matches the rank order observed

568

for MPD analysis.

569

It is interesting to observe that the thermal characterization results (Figure 4, 5 and 6)

570

have been negatively affected by the presence of SDS and P188. Also, as shown in Figure 8

571

and 9, the increased crystallization rate of amorphous drugs during dissolution incorporating

572

surfactants could be attributed to their higher affinity for water that could act as plasticizer.

573

The negative impact of surfactant is believed to be due to reduction in glass transition

574

temperature (Table 2) and also may be due to molecular effects possibly promoting polymer

575

chain entanglements and polymeric globule formation.51 The globules formed in the spray

576

drying solution seemed to be present in the solid state, and therefore, diffusion of the drug is

577

reduced. This indicates the presence of a memory where incorporation of surfactant in the

578

liquid state (spray drying solution) in polymer chain remained even after the solid particles

579

have had formed.

580

Towards this end, we have conducted 2D-NOESY experiments to understand the

581

surfactant-polymer interaction in the solution state (spray drying drug-polymer-surfactant

582

solution and also during dissolution). It provides information on the distance between protons

583

that are spatially close to each other.52 We observe the difference in 2D-NOESY spectra of

584

polymer compared to the spectra of polymer-surfactant combination (see supplementary

585

information). However, due to very small concentration of surfactant in the solution (to keep

586

the surfactant concentration same as used for dissolution experiments) the magnitude of

587

differences observed are very small. Similar effect of surfactant on PVP and HPMC have 19 ACS Paragon Plus Environment


Page 20 of 45

588

been reported previously.52 53 54 Nevertheless, these considerations are in agreement with the

589

results obtained from solid-state thermal analysis and in-vitro dissolution which suggests that

590

surfactant is competing with the drug molecules for polymer functional groups and thereby

591

reducing the crystallization inhibition efficiency of the polymer.

592 593

3.4. Moisture sorption analysis and Stability studies To further understand the behaviour of multi-component (binary, ternary and

594

quaternary) ASDs in the presence of moisture under stress conditions, the freshly prepared

595

spray dried dispersions were exposed to DVS analysis using double ramp method from 0-90-

596

0% RH (2 cycles) in 10% increments (dm/dt = 0.001 at each step) at 40 °C. As can be seen in

597

Figure 12, the amount of water uptake was greater in PVP based dispersions compared to

598

HPMC or PVP-HPMC based systems. This could be due to the more hydrophilic nature of

599

PVP compared to HPMC. Furthermore, the effect of surfactants on the moisture sorption

600

profile was greater in PVP based dispersions compared to HPMC or PVP-HPMC based

601

systems (Figure 12). Also, the time required to complete the double sorption-desorption cycle

602

varied significantly in different systems which suggests incorporating surfactant within the

603

dispersion significantly affects the moisture sorption ability of drug-polymer or drug-

604

polymer-polymer systems. This could be due to differences in the surface energy and

605

relaxation of amorphous API at the surface.53 It has been reported that structural relaxation at

606

the surface can vary significantly from relaxation in the bulk of amorphous materials.54

607

Surfactants get localised at the surface of the particles, affecting the relaxation energy and

608

consequently the crystallization rate.51 Furthermore, the Tg of the systems decreased when the

609

surfactants were incorporated within the dispersions (freshly prepared) which could suggest a

610

plasticization effect (refer supplementary information for

611

Crystallization was evident (post DVS cycles, Figure 12) in DPM-PVP-SDS, DPM-HPMC,

612

DPM-HPMC-SDS and DPM-HPMC-P188 dispersions signifying altered drug-polymer

613

interaction due to moisture sorption and surfactant incorporation. Other dispersions showed

614

no signs of crystallization. Similar results were observed for CNZ ASDs (data not shown).

615

These observations are in accordance with the previous DSC analysis and dissolution results

616

of freshly prepared dispersions.

mDSC thermograms).

617

We have previously reported that the amorphous forms of pure DPM and CNZ tend to

618

recrystallize rapidly in the absence of stabilizing polymers.11 We have also shown that

619

recrystallization of amorphous drug is delayed within ASDs.19 In this study, the physical

620

stability of multi-component ASDs was assessed under storage conditions of 40 °C/75% RH 20 ACS Paragon Plus Environment

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621

for 4 weeks (Figure 13, 14 and 15). The melting enthalpies of the crystallized samples are

622

provided in Table 2. The full DSC thermograms of stability samples are provided in

623

supplementary information. As shown in Figure 13, DPM-PVP systems were found to be

624

completely amorphous after 4 weeks, both with and without surfactant. However,

625

amorphous-amorphous phase separation was observed in DPM-PVP, DPM-PVP SDS and

626

DPM-PVP-P188 systems. All HPMC based DPM dispersions (Figure 14 and Table 2)

627

underwent crystallization suggesting PVP is better in maintaining solid-state stability of

628

amorphous DPM compared to HPMC. The solid dispersions of ternary DPM-PVP-HPMC

629

remained amorphous with significantly higher Tg values compared to binary dispersions

630

(Figure 15 and Table 2). This suggests a synergistic effect of polymer combination in

631

improving the solid-state stability of amorphous DPM. Further evidence of the synergistic

632

effect of PVP-HPMC was observed in case of CNZ dispersions where all CNZ systems

633

showed crystallization after 4 weeks of storage at 40 °C/75 % RH except CNZ-PVP-HPMC

634

dispersion (Figure 13, 14, 15 and Table 2).

635

Similar observations have been made in the past where surfactants had a negative

636

impact on the solid dispersion performance.51 Difference in the physicochemical properties of

637

SDS and P188 suggest that these events are controlled by the type of surfactant used. Thus, in

638

this study, we observed surfactants (when they are incorporated within the dispersions)

639

neither improved the solid state stability (Figure 4, 5, 6, 13, 14, 15 and Table 2) nor increased

640

the supersaturation level during dissolution (Figure 8 and 9). We found, in this case, that

641

drug-excipient and excipient-excipient interaction could have considerable impact on the

642

crystallization of amorphous API. Different systems behaved differently when observed

643

under different conditions (DSC, dissolution, DVS or stability). Further investigations are

644

required to confirm the localization of surfactants within spray dried particles to have a better

645

understanding of how surfactants affect drug-polymer interactions. Nevertheless, the use of

646

surfactants (as solubilizing or wetting agents) in spray dried ASDs requires prudent

647

consideration.

648

On the other hand, drug-polymer-polymer ternary ASDs showed higher stability and

649

dissolution compared with binary ASDs. PVP K30 and HPMC K100 complemented each

650

other to provide enhanced stability as well as improved drug supersaturation. The synergistic

651

efficiency of these polymers when used in combination in ternary ASDs could be due to

652

greater DPM and CNZ miscibility in the ternary systems compared with the binary system as

653

confirmed by MPD analysis and also stronger drug-polymer interaction in the ternary 21 ACS Paragon Plus Environment


654

dispersions, as confirmed by Tg measurements (Table 2) and FTIR results. In solution, the

655

presence of molecular interactions between the drug and polymer is responsible for

656

generating and maintaining drug supersaturation for a prolonged period of time (Figure 10

657

and 11). Similarly, crystallization of amorphous drug in solid state requires favourable

658

orientation for the crystal nucleation. It has been confirmed that surface crystallization occurs

659

at relatively faster rate compared to bulk crystallization.25 In ternary systems, the presence of

660

two polymers might increase overall entropy of the system by providing a barrier for

661

crystallization in surface and bulk. This is confirmed by the stability studies of CNZ-PVP-

662

HPMC system (Figure 15 and Table 2) which showed it was stable after exposure to moisture

663

for 4 weeks whereas all other CNZ system showed drug crystallization. Ternary dispersions

664

are complicated systems where weak drug-polymer interactions are involved in the

665

amorphous drug solubilisation and stabilization. Further molecular level investigations are

666

required to obtain a mechanistic understanding of the synergistic effects reported in this

667

study. Future work should investigate the interactions between additives and drug nuclei or

668

crystal surfaces, which had previously been reported as a critical factor of crystallization

669

inhibition or morphology modification.41 Also, more studies are required to examine more

670

drug-polymer combinations or the combinations of different additives including other

671

surfactants at different concentrations for synergistic effects using advanced characterization

672

techniques such as solid-state NMR, dielectric spectroscopy, inverse gas chromatography,

673

nucleation induction studies in the presence of moisture or during dissolution, and others.

674

These studies are currently underway in our lab and will form the basis of next article.

675

5. CONCLUSION

676

The incorporation of surfactants and polymer combinations seems to have a

677

significant effect on the properties of the resulting ASDs. Surfactants, when incorporated in

678

ASDs, resulted in altered dissolution rates, reduced stability and altered drug-polymer

679

interactions. The combination of PVP K30 and HPMC K100, two polymers which displayed

680

drug-polymer interaction, resulted in significant crystallization inhibition (both in solid-state

681

and dissolution) of the poorly soluble drugs DPM and CNZ. This enhanced crystallization

682

inhibition efficiency can be correlated to the synergistic effect of PVP K30 and HPMC K100.

683

This study also highlights the importance of utilizing ternary drug-polymer-polymer

684

interactions by combining polymers with different crystallization inhibition mechanisms for

685

improved solid-state stability and dissolution enhancement of poorly soluble drugs.


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686 687

688


NOTE The authors declare no competing financial interest.

ACKNOWLEDGEMENT

689

This publication has emanated from research conducted with the financial support of

690

the Synthesis and Solid State Pharmaceutical Centre, funded by Science Foundation Ireland

691

under Grant Numbers (SB, grant 12/RC/2275) as well as support from Waterford Institute of

692

Technology.

693 694 695

Supporting Information:

696

MDSC thermograms (fresh, stability and post-DVS samples), full NMR spectra and XRD

697

spectra have been provided in the supporting information.

698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714



715

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Figure 1. Chemical structure of DPM, CNZ, PVP K30, SDS, P188 and HPMC K100 (clockwise from top) 270x148mm (96 x 96 DPI)

ACS Paragon Plus Environment

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Figure 2. DSC thermograms of physical mixtures of model drugs and polymers at various drug loads; n = 3. Values in parentheses are % weight fraction. 215x140mm (96 x 96 DPI)



Figure 3. Experimental and theoretical depression in melting point of model drugs at various %w/w drug loading. 238x83mm (96 x 96 DPI)


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Figure 4. mDSC thermograms of freshly prepared DPM and CNZ ASDs with PVP; n = 3; Full DSC thermograms are provided in the supplementary information. 267x132mm (96 x 96 DPI)



Figure 5. mDSC thermograms of freshly prepared DPM and CNZ ASDs with HPMC; n = 3; Full DSC thermograms are provided in the supplementary information. 262x138mm (96 x 96 DPI)


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Figure 6. mDSC thermograms of freshly prepared DPM and CNZ ASDs with PVP-HPMC; n = 3; Full DSC thermograms are provided in the supplementary information. 261x138mm (96 x 96 DPI)



Figure 7. FTIR spectra of freshly prepared DPM ASDs 213x141mm (96 x 96 DPI)


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Figure 8. In-vitro dissolution profile of DPM ASDs in PBS 6.8 at 37°C with PVP (a), HPMC (b) and PVP-HPMC (c); samples equivalent to 25 mg of drug was added to PBS 6.8; Each point represents mean ± SD; n = 2 267x124mm (96 x 96 DPI)



Figure 9. In-vitro dissolution profile of CNZ ASDs in PBS 6.8 at 37°C with PVP (a), HPMC (b) and PVP-HPMC (c); samples equivalent to 25 mg of drug was added to PBS 6.8; Each point represents mean ± SD; n = 2 264x123mm (96 x 96 DPI)


Page 38 of 45

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Figure 10. Solution 1H NMR spectra of DPM (1000 µg/mL) in DMSO-d6. Figures in inset represent the chemical shift of DPM (a), DPM-PVP (b), DPM-HPMC (c), and DPM-PVP-HPMC (d). The numbers at top of each inset figure represent the peak number in DPM spectra. Assignments of DPM resonance is based on spectral database [49]. Numbers are assigned arbitrarily 253x142mm (96 x 96 DPI)



Figure 11. Solution 1H NMR spectra of CNZ (1000 µg/mL) in DMSO-d6. Figures in inset represent the chemical shift of CNZ (a), CNZ-PVP (b), CNZ-HPMC (c), and CNZ-PVP-HPMC (d). The numbers at top of each inset figure represent the peak number in CNZ spectra. Assignments of CNZ resonance is based on Sassene et al.[50]. Numbers are assigned arbitrarily 234x144mm (96 x 96 DPI)


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Figure 12. DVS analysis of freshly prepared DPM ASDs with PVP (a), HPMC (b) and PVP-HPMC (c) using double ramp method from 0-90-0% RH (2 cycles) in 10% increment (dm/dt=0.001 at each step) at 40 °C; DSC thermograms (d) of DPM ASDs post DVS double cycle 212x141mm (96 x 96 DPI)



Figure 13. mDSC thermograms of stressed DPM and CNZ ASDs with PVP; n = 3; Full DSC thermograms are provided in the supplementary information 254x139mm (96 x 96 DPI)


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Figure 14. mDSC thermograms of stressed DPM and CNZ ASDs with HPMC; n = 3; Full DSC thermograms are provided in the supplementary information 256x140mm (96 x 96 DPI)



Figure 15. mDSC thermograms of stressed DPM and CNZ ASDs with PVP-HPMC; n = 3; Full DSC thermograms are provided in the supplementary information 252x137mm (96 x 96 DPI)


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Graphical Abstract 211x141mm (96 x 96 DPI)


Investigation into the Solid-State Properties and Dissolution Profile of

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