Exploring the Role of Amorphous Materials in Drug Formulations

Bernal Seminar Prof Anne Marie Healy: The Amorphous State–Friend or Foe of the Formulation Scientist

Estimated read time: 1:20

Summary

In this insightful seminar, Prof. Anne Marie Healy delves into the dual nature of the amorphous state in pharmaceutical formulations. Through a comprehensive analysis, she explains the potential advantages and challenges associated with amorphous materials. Prof. Healy elaborates on the significance of the glass transition temperature (Tg) and shares strategies to harness the benefits of amorphous states while mitigating their risks. The discussion extends to the use of amorphous solid dispersions in enhancing drug solubility and bioavailability, particularly for challenging compounds in the pharmaceutical development pipeline. The seminar also touches on techniques and practical considerations for formulation scientists dealing with amorphous materials.

Highlights

Prof. Healy explores whether the amorphous state is a friend or foe to formulation scientists. 📊
The seminar covers the importance of the amorphous state and its characteristics, including the glass transition temperature. 🔍
Amorphous materials show a lack of long-range order but possess advantages like improved solubility and dissolution rates. 💧
She discusses the challenges like physical instability and how to use stabilizers to extend the amorphous state. 🛠️
The talk emphasizes the growing acceptance and implementation of amorphous solid dispersions in the pharmaceutical industry. 🌐

Key Takeaways

The amorphous state can be both a friend and foe in drug formulations, offering solubility benefits but with stability challenges. 🤔
Understanding and manipulating the glass transition temperature (Tg) is crucial for stabilizing amorphous forms. 🌡️
Amorphous materials can significantly enhance drug solubility and dissolution rates, which is beneficial for bioavailability. 💊
Amorphous solid dispersions are becoming more popular as they help manage solubility challenges in pharmaceuticals. 📈
Selecting the right polymer is essential for stabilizing amorphous drug forms both in solid and solution states. 🧪

Overview

During her seminar, Prof. Anne Marie Healy navigates the complexities of the amorphous state, a critical yet challenging aspect of pharmaceutical formulation. By contrasting crystalline structures with amorphous materials, she highlights their unique characteristics, particularly focusing on the importance of controlling the glass transition temperature to manage the stability and performance of drugs.

The seminar underscores the potential of amorphous materials in enhancing drug solubility, especially for compounds with poor dissolution rates. By using techniques like spray drying and hot melt extrusion, formulation scientists can create amorphous solid dispersions to improve bioavailability.

Prof. Healy also discusses strategies to overcome the downsides of working with amorphous substances, providing insights into the selection of polymer excipients for better stability and solution endurance. This nuanced understanding helps tailor the formulation process, ensuring efficacious and stable pharmaceuticals.

Chapters

00:00 - 01:00: Introduction and Overview The introduction and overview of the seminar series, delivered by the speaker who was kindly introduced by Sarah and invited by Edmund, focuses on the topic of 'The Amorphous State: Friend or Foe of the Formulation Scientist'. The initial slide outlines the presentation's structure, aiming to cover the characteristics and implications of the amorphous state. The session's purpose is to delve into the knowledge of the amorphous state, pertinent to many within the audience.
01:00 - 06:00: Characteristics of Amorphous Materials The chapter discusses the characteristics and significance of amorphous materials, exploring why they are of interest in various fields. It highlights the dual nature of amorphous materials, which can be advantageous or detrimental depending on the context. There is a focus on clarifying what is meant by the amorphous state for those who are unfamiliar. The chapter further elaborates on both the positive and negative attributes of amorphous materials, detailing what makes them noteworthy.
06:00 - 12:00: Amorphous State in Formulation Science The chapter on 'Amorphous State in Formulation Science' discusses both the positive and negative aspects of amorphous materials. It explores how the benefits of these materials can be harnessed in formulations while also considering strategies to mitigate the drawbacks associated with handling and incorporating them in various applications.
12:00 - 18:00: Benefits and Challenges of Amorphous State In this chapter, the concept of amorphous materials is explored. Amorphous materials are defined as those that lack the three-dimensional long-range order characteristic of crystalline forms. They are sometimes described as extremely viscous liquids or as liquids that have lost their ability to flow, emphasizing their unique lack of structure.
18:00 - 24:00: Generation of Amorphous Materials The chapter discusses the characteristics of amorphous materials, which lack long-range order but possess some short-range order. Unlike crystalline materials that have a repeating ordered structure, amorphous forms are more disordered. The discussion compares the structural differences between crystalline and amorphous materials, highlighting that an amorphous material represents a disordered solid-state form.
24:00 - 30:00: Using Amorphous Materials to Improve Bioavailability The chapter discusses the concept of amorphous materials and their application in improving bioavailability.
30:00 - 36:00: Amorphous Solid Dispersions (ASDs) The chapter discusses Amorphous Solid Dispersions (ASDs), focusing on the behavior of melts and their cooling processes. It explains the concept of the super cooled liquid state, which occurs when a melt is rapidly cooled to avoid crystallization, leading to a dense, viscous equilibrium liquid form. The chapter also contrasts this state with the glassy state, emphasizing the significance of cooling rates in determining the final structure of the solidified material.
36:00 - 48:00: Polymer Selection and Process Influence The chapter focuses on the concept of glass transition temperature, which is crucial in understanding the behavior of amorphous compounds. When a material, specifically an amorphous one, is cooled and passes a particular temperature, it enters a 'glassy state.' This glassy state represents a solid, non-equilibrium form of the material. The glass transition temperature is the point at which the material changes from a supercooled liquid, also referred to as a rubbery state, to this glassy state. This transition is key in polymer selection and processing.
48:00 - 54:00: Avoiding Unintentional Amorphous Generation The chapter titled 'Avoiding Unintentional Amorphous Generation' focuses on the importance of the glass transition temperature (Tg) when dealing with amorphous materials. Tg is a critical parameter that signifies the stability of these materials, as well as the appropriate storage conditions to maintain their stability. The chapter emphasizes the necessity of understanding and managing Tg to prevent inadvertent formation of amorphous structures.
54:00 - 60:00: Audience Questions and Discussion The chapter discusses the importance of keeping materials at a temperature approximately 50 degrees lower than their glass transition temperature to maintain a stable amorphous form. It emphasizes that knowing the glass transition temperature can give confidence in the material's physical stability at room temperature, which is beneficial for handling and manipulating amorphous materials.

Bernal Seminar Prof Anne Marie Healy: The Amorphous State–Friend or Foe of the Formulation Scientist Transcription

00:00 - 00:30 thank you very much uh sarah for a very kind introduction and thank you to edmund for the invitation to speak at uh this seminar series um so uh as sarah said that the the title of my talk is the amorphous state friend or foe of the formulation scientist and um this slide just gives you an indication of the outline of the presentation and what i hope to cover in in the time that we have available today so um many of you will know a lot about the amorphous state and
00:30 - 01:00 what it is and why it's of interest to us um and how it can potentially be our friend or potentially be our our foe um but i'll i'll speak a little bit about just explaining for those of you who don't know so much about it what we mean by the amorphous state and why it's of interest and i'll go on then to look at some of the characteristics of amorphous materials um the good and the bad um so what makes uh the amorphous state of interest to us
01:00 - 01:30 and and both from a positive and a negative perspective i guess and then look at you know how we can harness the good aspects of amorphous materials and make use of amorphous materials um in our formulations and conversely then how we can avoid um some of the bad aspects of handling and dealing with amorphous materials um
01:30 - 02:00 so first of all what what do we mean by um amorphous materials or what are amorphous systems so an amorphous material is a material that unlike crystalline forms uh lacks three-dimensional long-range order um and it has been described as a liquid that has lost its ability to to flow or an extremely viscous liquid so while amorphous materials possess no um
02:00 - 02:30 three-dimensional long-range order they do have some short-range order um so if this schematic here represents a piston material and and this and the morphs material you see that the morphs form is much more disordered uh so it's a disordered uh solid-state form um so if we think of a crystalline material or something like this you know nice repeating ordered um crystal structure um
02:30 - 03:00 an amorphous material might look something more like this significantly more disordered and chaotic perhaps key aspect of amorphous materials that we need to [Music] be aware of particularly when it comes to trying to formulate amorphous compounds and amorphous forms is the glass transition temperature um so amorphous solids can exist in two states
03:00 - 03:30 and we have what's called the super cool liquid state and we have a glassy state and so if for example we start off with with a melt and you and you slowly cool that melt um you will get crystallization but if you rapidly cool the melt you can avoid arrangement into crystal form and instead produce what's called the super cooled liquid state so this super cool liquid state is a viscous equilibrium liquid form of
03:30 - 04:00 the material once you pass a particular temperature which is characteristic of an amorphous compound you can enter into what's called the glassy state which is a solid non-equilibrium form of the same material and the temperature at which you get this change from a supercooled liquid or sometimes called a rubbery state to a glassy state is this glass transition temperature or the
04:00 - 04:30 tg um and the glass transit transition temperature is very important uh to know as i said when we're handling or using amorphous materials because it's an indicator of the stability of the material and an indicator of the storage conditions at which we can maintain stability of the amorphous form and so as a rule of thumb for example if we can store
04:30 - 05:00 our material at a temperature around 50 degrees less than the glass transition temperature we should have a reasonably physically stable amorphous form and that means that if we have a material and we know its glass transition temperature is high we can have reasonable confidence that at room temperature for example it'll have pretty good physical stability so in terms of handling and manipulating amorphous uh materials
05:00 - 05:30 um some of our interest in in a formulation context is to try and elevate the glass transition temperature or to keep the glass transition temperature relative to the storage temperature high enough that we maintain physical stability and i'll come back to that a little later so some characteristics of amorphous materials um how do we know we have an amorphous form well as i said
05:30 - 06:00 these amorphous forms they don't project possess long-range uh three-dimensional order but they do possess short-range order so one quick easy check to see have you amorphous material there or have you some amount of amorphous or non-crystalline material there is to look at it on a powder x-ray diffraction and while the crystalline material will give you these nice distinct black peaks with an amorphous form of the same material we'll see what's referred to as this
06:00 - 06:30 amorphous halo so much more diffuse pattern in the px2 now on the downside i've mentioned this issue of the glass transition temperature and how it relates to the physical stability of the amorphous form on the downside amorphous materials tend to be less physically and also less chemically stable than their crystalline counterparts and they also tend to have altered process ability and a lot of that altered process ability so handling in
06:30 - 07:00 the various pharmaceutical processes that we have to put materials through in drug product production um a lot of that processability uh relates to the fact that amorphous materials and well they they tend to suck in a lot of moisture so any moisture in the atmosphere that makes them sticky it also makes them unstable um and you have to be very careful about the
07:00 - 07:30 handling of the materials and the temperature at which they're handled vis-a-vis their glass transition temperature however on the plus side and why um we're interested in harnessing um the good aspects of morphs materials is they do have higher apparent solubility and faster dissolution rates than their crystalline counterparts so they are hot a higher energy form and because they're a higher energy form they have higher solubility faster
07:30 - 08:00 dissolution rates and so for drugs where the this is problematic um if we can use the drug in its amorphous form we can improve these critical characteristics of the drug and the formulation performance so in forms of product development and manufacture the amorphous state may be purposefully generated to harness the positive aspects of amorphous materials but we also need to be aware that it can
08:00 - 08:30 be unintentionally generated and when it's unintentionally generated it can impact on the stability of our drug and of our drug product and can also impact on the processability ways in which we can generate amorphous material as i said both intentionally or unintentionally in a pharmaceutical manufacturing context would be by precipitation from solution
08:30 - 09:00 uh or by disruption of the crystalline lattice and so these are sometimes referred to as a bottom-up or or a top-down process in terms of intentional generation of the amorphous form things like solvent evaporation spray drying freeze drying cold precipitation can be used um but unintentionally we can sometimes get amorphous form being generated in in other pharmaceutical processes uh that
09:00 - 09:30 we're subjecting our what we hope will will remain a crystalline material to and that's things like wet granulation drying or film coating we can also intentionally generate amorphous materials by grinding or milling processes but again in a pharmaceutical manufacturing context often these processes like grinding um unintentionally generate amorphous material or an amount of amorphous material in a largely crystalline uh
09:30 - 10:00 form and other com other processes like desolvation and compaction likewise and can unintentionally generate some level of disorder or amorphous material in a larger crystalline material okay so having said that you know there's both positive and negative aspects to the amorphous state or to the amorphous form how do we harness the positive aspects how do we harness the good elements uh so that we
10:00 - 10:30 associate with amorphous materials and why do we want to do so um well one reason why we want to use amorphous materials uh relates to improving bioavailability from oral knowledge dosage forms so for example if we start off with a disintegration tablet formulation that tablet when a patient takes it will break up onto smaller parts from those smaller parts the active pharmaceutical ingredient will dissolve or will go into
10:30 - 11:00 solution and it is only when the drug is in solution that it can be absorbed that it can pass through the gut wall and get into the systemic circulation and in the systemic circulation then the drug makes its way around the body reaches the receptors where it will have its pharmacological effect and ultimately you get therapeutic clinical benefit um what happens if the drug doesn't get into solution well if it doesn't get into solution
11:00 - 11:30 then this can't happen it can't pass through the wall of the gi tract it won't get into the systemic circulation you won't get an effect and for many many drugs and increasingly for drugs that are coming through the product development cycle we're seeing that a lot of these drugs fall into what's called the bcs class 2 and class 4
11:30 - 12:00 categories and and this is the biopharmaceutical classification system and in both bcs class 2 and class 4 we have drugs that have an issue with their solubility right so um and if drugs have low solubility um then there's going to be an issue with them dissolving in the gastrointestinal tract and we're going to have problems with um bioavailability because insufficient
12:00 - 12:30 drug will get into the systemic circulation um so class two drugs are ones where we have low solubility but high permeability so it's only really the solubility aspect we have to try and manipulate we also have class 4 drugs which are even more difficult to deal with because they have low solubility and low permeability but how do we overcome this issue of low solubility to improve uh or with a view to improving
12:30 - 13:00 bioavailability um well there's a range of different approaches that can be used um [Music] and these are chemical processes physical process or or process involving complexation and so amorphization is one of the strategies that we can use to improve solubility because we're generating this higher energy form that has increased solubility relative to the
13:00 - 13:30 crystalline equivalent and so we can purposely generate the amorphous state of the same pharmaceutical compound improve its solubility improve its dissolution rate and ultimately we would hope improve the bioavailability for these challenging bcs class 2 and potentially also bcs class 4 compounds so the solubility of the amorphous form and the higher solubility of the
13:30 - 14:00 amorphous one relative crystalline form is an aspect that we as formulation scientists look to harness to improve the performance of our products when we're dealing with these poorly soluble drugs and if we look here this is an example of a drug sulfidimidine um where the raw material which is the crystalline form um has a pretty low uh solubility
14:00 - 14:30 um that solubility is increased when we convert it to the spray dried amorphous form and is doubled in a in water where we have uh pvp polyphenol paralladon in the water dissolved in the water as well and it will become clear a little later on why this is important compared to when we just look at the solubility in water on its own we don't see much difference between the crystalline
14:30 - 15:00 and the amount of snow but this is the dynamic solubility profile where we see the significant difference between the crystalline and the amorphous form in terms of the solubility um and this then translates to a significant difference in the dissolution profiles from the amorphous which is the red profile and the crystalline form and in the case of some drugs this difference in solubility
15:00 - 15:30 is quite significant between the amorphous and crystalline form leading to significantly different dissolution profiles and so for example this is an example of rotanovir in the crystalline versus the amorphous form and this is looking at what's called intrinsic dissolution rates where we keep the surface area constant so it's not a particle size effect or anything like that it's a purely a solubility effect and we're seeing a
15:30 - 16:00 tenfold increase in the in the dissolution rate so significant dissolution rate enhancement can be achieved by using the same drug but in a different solid state form and there are some commercial products where the amorphous form of the drug is used in what we might call a conventional type formulation um as opposed to some of the enabling formulations that i'll come to a little
16:00 - 16:30 later on but with with these um formulations the drug is presented in an amorphous form but not in an amorphous solid dispersion form which is a more common way of presenting amorphous drugs as enabling formulations which i which i would come to but with these drugs if you're going to use the amorphous form of the drug in a conventional formulation you have to be pretty sure that the drug is going to
16:30 - 17:00 say stay stable and stay in the amorphous state for the life or for the shelf life of the product and to ensure that that happens the amorphous form of the drug has to have a reasonably high glass transition temperature and have been proven to stay physically and chemically stable so there are relatively few drugs that fit that bill
17:00 - 17:30 now it's not to say that there aren't other formulations of other drugs where the drug is presented in the amorphous form but with these other formulations they are enabling formulations where the drug is presented in the form of what's called an amorphous solid dispersion and i'll explain now why we need to consider um developing these drugs as amorphous dispersions so this is a very nice article that was
17:30 - 18:00 presented by alonso back into 2010 and they were looking at uh philodipine as a model drug and looking at the dissolution profiles of amorphous phelodipine versus crystalline phloempine and looking at the dissolution at two different temperatures 25 degrees centigrade and 37 degrees centigrade and different concentrations of um the powder um
18:00 - 18:30 but interestingly what was found here is that while the at 25 degrees centigrade you get this huge uplift if you like in the dissolution profile initially and then it kind of falls away at 37 degrees centigrade and with the same concentration of amorphous material as crystalline material there's really no difference in the dissolution profiles so the purple where i've drawn the purple line here that's the amorphous
18:30 - 19:00 uh form at the same concentration as the crystalline one uh which it it more or less overlays sorry actually the crystalline one is the one that i've drawn the purple line in but you see the amorphous one is just sitting just underneath it so they're pretty much equivalent at 37 degrees and why is that the case well it's because if you look at the transformation kinetics so this group used ram and spectroscopy to see what was happening to the solid material in the course of the dissolution profile
19:00 - 19:30 and they see that at 37 degrees centigrade you're getting very rapid crystallization so the drug the amorphous form of the drug is crystallizing really before it's getting a chance to dissolve whereas at 25 degrees centigrade that crystallization is so with that you get you do get this benefit of the higher solubility in the higher dissolution rate of the amorphous form at 25 degrees but not at 37.
19:30 - 20:00 so in terms of using the amorphous form of drug and and in harnessing the benefits provided by the higher solubility of the amorphous form um we need to be concerned with uh keeping the drug in the amorphous state okay so if we have the drug in solid state what we want to do is prevent crystallization of that form of the drug
20:00 - 20:30 um if we get the drug to to present in solution so to dissolve and give us a supersaturated solution which is what we'd hope to get from the amorphous form we want to prevent that supersaturated solution from nucleating too quickly and giving us the crystalline form too quickly so we want to get good supersaturation but we want to maintain that supersaturated solution and we want
20:30 - 21:00 to avoid crystallization from this solid state of the formulation as well and this is is where we look to use components in our formulation excipients in our formulation that will either stop this from happening or stop this from happening and typically uh these are polymeric recipients so in
21:00 - 21:30 terms of stabilizing the amorphous form in the solid state we can look at storage at low temperatures as i said maybe 50 degrees below the glass transition temperature or we can use polymeric excipients and these same polymeric excipients then when we introduce the formulation into the liquid state should also we would hope um prolong the supersaturation of in the
21:30 - 22:00 solution that we see and prevent crystallization from the matrix so these polymeric excipients how do they act to improve the stability of the amorphous form well they can increase the glass transition temperature and this is what's known as an anti-plasticizing effect if we get hydrogen bonding interactions between the the drug and the polymer and that um further enhances the the reduction in the molecular mobility
22:00 - 22:30 uh which improves the stability of the amorphous form and we also kind of get this barrier to diffusion presented by the polymer being intimately mixed with the drug molecules and so we get this barrier to diffusion which inhibits this nucleation and crystallization so this is where we come to look at these of solid dispersions as um appropriate formulations for
22:30 - 23:00 amorphous drugs and the early literature referred to salt dispersions as just mixtures of polymer and crystalline drugs actually and and even when the drug was in the crystalline state if the particle size was small enough and if there was an intimate mix between the drug and the polymer you do get you did get some enhancement of dissolution but increasingly now more it's a more facile dispersions that we're concerned with where we have an intimate mix of drug
23:00 - 23:30 and polymer at the molecular level and so we have what's often referred to as an amorphous dispersion or an amorphous solid solution or sometimes a molecular dispersion because we have this uh intimate mixture at the molecular level ideal scenario is one like this so we have this solid solution of draw intimately mixed with polymer what we would look to avoid is that we get phase separation where we get a
23:30 - 24:00 separation of the crystalline phase from the polymer phase or what we also like to avoid is phase separation even when we don't yet have full crystallization but we get phase separation in two separate amorphous phases so we have a polymer rich phase and a api rich phase because the the introduction of phase separation even when there are morphostates is more likely to move to a scenario where we
24:00 - 24:30 have phase separation with drug in the crystalline form which is what we want to avoid so with amorphous solid dispersion we have introduced a polymer into the system which should stabilize the amorphous scrub resulting in better physical stability in the solid state but also as i said when we introduce these formulations into the liquid into the liquid of our gastrointestinal tract particularly that we'll get higher
24:30 - 25:00 apparent solubility faster dissolution and ultimately improved bioavailability from these and hard to manage or hard to handle drugs up with poor solubility in a pharmaceutical manufacturing context amorphous solid dispersions have largely been produced to date by one of two methods and that's spray drying or hot melt extrusion
25:00 - 25:30 and this just presents a timeline of um regulatory approval of some of these amorphous solid dispersions and you'll see that you know things started off pretty slowly but even you know as far back as the mid 1980s we saw some of the first of these um formulations coming on the market and then there was really an explosion of these asd formulations in the um i suppose the late 2000s and going up as far as well
25:30 - 26:00 this only shows it going as far as 2016 but it has continued up to uh current date and i suppose this just demonstrates that you know pharmaceutical companies initially perhaps were very hesitant to to look at the amorphous form as a viable option for their products um but as there's been an increased understanding of the amorphous state and amorphous formulations there is a growing i would say
26:00 - 26:30 level of comfortableness if that's the correct word of handling using and producing amorphous materials and more facilities versions that have found their way into uh commercial production as i said so this uh this table here shows um the range of different commercially available amorphous solid dispersions at the dosage form in which they're presented and also the
26:30 - 27:00 manufacturing methods that's used and and as i said in most cases it's either spray drying or hot melt extrusion that that have been used to date although there are other options for example uh precipitation or co-precipitation and sugar spraying sorry spray drying or spray coating on sugar beads so coming back to this scenario where we were looking at the amorphous philodipine and this issue of okay well at the lower
27:00 - 27:30 temperature we do get some level of supersaturation into the liquid but it's not really maintained and at the higher temperature we get such rapid crystallization um from the solid state that we really see no benefit from using the amorphous form at all the same group looked to see well what happens when you put some polymer into the liquid into which you're looking for your amorphous form
27:30 - 28:00 to dissolve and they found that well if you introduce some polymer at least the right polymer into the liquid you can actually maintain um the level of supersaturation for much longer and you can get the supersaturation uh to occur not only at 25 degrees centigrade as they saw previously but also now at 37 degrees centigrade and looking at the transformation kinetics the transformation kinetics in
28:00 - 28:30 terms of the conversion from the amorphous to the crystalline state is much delayed in the presence of these various polymeric excipients so this effect of having the polymer there and then the polymer going into solution along with the amorphous form of the drug provides what's um commonly referred to as the spring and parachute effect so what we want is to get this spring
28:30 - 29:00 this high uh rate of dissolution and um presentation of a supersaturated solution which we can get from the amorphous form but the polymer then is what provides the parachute to extend that drug concentration in solution in the supersaturated state so that it doesn't crash out immediately and so we get this this extended supersaturation which provides
29:00 - 29:30 for greater opportunity than for absorption in vivo in the gastrointestinal tract and if we keep that supersaturated solution of the drug that was initially in the amorphous solid state form and so this is the advantage that's provided by these amorphous solid dispersion formulation and there are a range of different polymers that can and have been used in
29:30 - 30:00 in these uh different formulations and so the question is well how do you pick the right polymer or is there a right polymer for a particular drug and in reality the polymer selection is still largely based on on trial and error approaches and you know there are some polymers that are more suited to spray drying versus hot melt extrusion for example um
30:00 - 30:30 but to match a polymer with a particular drug you have to take into account things like glass transition temperature the solubility the thermal the lability the molecular rate the hydroscopicity and so on and but we are looking for a polymer or combination of polymers that will have the ability to maintain the drug in the amorphous form in the solid state so during manufacture and storage and shipment but also maintain the supersaturated solution state when the
30:30 - 31:00 drug is is presented in vivo and goes into solution in the body so that we get good absorption from that formulation what makes a good polymer in endomorphologist version well this just shows one example of where we looked at spray drying a range of thiazide compounds with pvp as as the polymer and if you look at the the thermal analysis
31:00 - 31:30 of these systems so um if we just sprayed right the drugs on their own so that's uh the thermograms are shown in abc here we see uh this exotherm here this exotherm represents uh recrystallization of the amorphous form right so it crystallizes when we heat it and then we get um melting endotherm in the solid dispersions that have been sprayed right with polymer you see you don't get this exothermic so they are thermally at
31:30 - 32:00 least thermally stable we're not getting this recrystallization exiting if we look at the glass transition temperatures um relative to the weight fraction of polymer that we use we see actually so the the squares or the triangles the the symbols here are the experimental profiles and and the the the lines or the curves are are modeled the glass transition temperatures but the experimental profiles are i guess what are
32:00 - 32:30 interesting we see that we can get significantly higher glass transition temperatures than is predicted by simple models which don't incorporate any level of interaction between the drug and the polymer where we do get hydrogen bonding interaction in particular between drug and polymer we can significantly shift the glass transition temperature upwards and that provides for significantly improved stability of our amorphous solid
32:30 - 33:00 dispersion we can if we look at um these types of phase diagrams where we're looking at the glass transition temperature and we're looking at the solubility of the drug in the polymer we can look at these phase diagrams to pick out regions where we should have maximum stability of drug in polymer in these amorphous salt dispersions because
33:00 - 33:30 ideally we want to be below the super saturation level of the drug in the polymer and below the glass transition temperature where we minimize the molecular mobility so there there are kind of ways in which we can more rationally design our amorphous solid dispersions rather than just kind of using a trial and error approach some more recent work that one of my phd students did was looking at um you know
33:30 - 34:00 how if we're looking at a particular polymer how do we pick within a range of different options and this is for and pvp va within a range of different options how do we pick the best polymer to give us good stability but also good uh dissolution performance and the polymer itself and subtle differences in the polymer that we choose can provide for very different performance characteristics of the asd so for example here the molecular weight
34:00 - 34:30 of the polymer can give us different dynamic solubility profiles the ratio of the uh vinyl paralladon to vinyl acetate in the polymer can give us significantly different dynamic solubility profiles and so in this work the student is looking you know for a particular polymer um what will be the effect on the asd performance of the molecular weight the in this case vinyl acetate versus uh
34:30 - 35:00 vitamin content and how can we relate the characteristics of the polymer to the asd performance um so i guess this is with a view to moving away a little bit from just you know a trial and error approach where we stick in a load of different polymers with different drugs mix them up process them by different means and see what we get is can we be a little bit clever about the selection of our polymer constituent
35:00 - 35:30 the other thing we have to worry about then is the process you know what process are we going to use to generate the asds and as well as the polymer the process can have an effect on the ultimate performance characteristics of our asd so here we need to think about the solubility of both the api and the polymer this thermal stability of the api and the polymer what loading of api are we looking for what scale are we looking to work at and do we want to work in a batch or continuous process
35:30 - 36:00 but even with the same drug polymer combination we can see that two different processes can give us quite different results so this is an example where we looked at spray drying versus milling for the same drug polymer combination but we see that with the top down approach spray drying we can produce amorphous uh asd
36:00 - 36:30 at a much lower polymer composition than we can hope to achieve with the um [Music] sorry the the spray drying of course is the bottom up the milling is the top down approach so with milling we need to use a lot more polymer to get the same outcome in terms of an amorphous solid dispersion that appears to be amorphous on the pxod and this was demonstrated for two
36:30 - 37:00 different drugs if we do manage to get an amorphous cell dispersion whichever form or whichever process we use to generate it the performance characteristics of the asd for these two different drugs with the same polymer um ultimately end up being equivalent so this is looking at dissolution rate enhancement um for coal milled versus spray drive materials initially
37:00 - 37:30 uh dissolution rate enhancement and limiting to solution rate enhancement another process that we're currently working on and looking to compare um is co-precipitation and looking to compare how does co precipitation um match up to spray drying uh which i guess is a more more commonly used approach um and i'm not to dwell on this um but again we see that
37:30 - 38:00 for this particular drug polymer combination because there's a significant opportunity for a hydrogen bonding interaction we get high glass transition temperatures much higher than the model predicted and regardless of the process we get in this case um amorphous solid dispersion that are equivalent by pxod and by uh largely equivalent by dlc
38:00 - 38:30 okay i've focused a lot on um you know how do we how do we harness the good aspects of amorphous all dispersions and in the last i guess five minutes or so i'm going to speak a little bit about um well how do we avoid the bad and i guess this is more so if okay we we perhaps don't have an issue with solubility of a drug we want to maintain the drug in a large crystalline form um
38:30 - 39:00 we don't have want to have to worry about using an amorphous form of the drug because we don't want to worry about its physical instability perhaps um and so on so how do we avoid generating or unnecessarily or unintentionally generating the amorphous form in a largely crystalline material and why do we want to avoid it and so this is really just a repetition of what i said already but
39:00 - 39:30 one of the concerns of using amorphous materials is their inherent physical instability they will inevitably try to crystallize to get to the lower energy crystalline state and this can occur um you know either relatively slowly so this shows a a material which is stored for one year at a relatively high unity and and on px or d eventually does show a level of
39:30 - 40:00 crystallization or it can occur much more quickly so this shows another drug which when we spray dry it initially and do a dsc really quickly it shows that it's amorphous because we get the recrystallization extern on the dnc but after an hour it has crystallized uh to a particular polymer polymorphic form so sometimes these amorphous materials are just you know not feasible to to manage or to
40:00 - 40:30 handle uh because they're just so physically unstable the other big problem with using amorphous materials and even small amounts of amorphous materials is that they love to suck in moisture from the atmosphere and this presents problems and can present problems with the processability of the powder becomes glomerated hard to handle and sometimes
40:30 - 41:00 just completely unprocessable we end up in this example of hydrochlorothiazide with uh pv pva and amorphosal dispersion if you expose it to high humidity you get this sticky gloopy mess um from what once was a nice free-flowing powder even if we have small amount of amorphous material sitting on the surface of particles that frequently is generated by mechanical
41:00 - 41:30 activation processes that we see in milling these small amounts of amorphous material on the surface of the particles they'll suck in moisture and that will lead to agglomeration as a result of solid or liquid bridge formation so one strategy that we looked at a little bit to try and overcome this is to use low glass transition temperature
41:30 - 42:00 recipients and to mix them intimately with and the amorphous form that we perhaps have unintentionally generated to get the excipient to trigger crystallization of the composite system so this is almost like a reverse of using the high glass transition to polymeric components to stabilize the amorphous form in this case we want to intimately mix at the molecular level
42:00 - 42:30 low glass transition temperature crystalline excipients with amorphous material that might be unintentionally generated to drive down the glass transition temperature of the composite material and trigger crystallization so that any amorphous material that's generated is only temporarily there and it's switched back to the amorphous form so here what we're looking at is mixing a crystalline api with an excipient
42:30 - 43:00 what happens when you mill that mixture if and compare that to what happens when you mill uh the crystalline api on its own if you mill it hard enough for long enough you can get it to become totally amorphous but actually if you pick the right excipient right excipient with low enough glass transition temperature you can um okay there may be temporary amorphization there but you can trigger
43:00 - 43:30 crystallization and so here this is just an example of sulfidimidine mixed with a range of different crystalline excipients at 50 50 ratio and we see that for one in particular glutaric acid which is a low glass transition temperature it can [Music] can prevent the amorphization of the mixture interestingly the uh hildebrand solubility parameters
43:30 - 44:00 of glutaric acid and our drug are very close so the difference between them is very very small and the excipient has a low glass transition temperature and we can actually use thermal methods to measure the solubility of the excipient or sorry the solubility of the excipient the crystalline excipient in the amorphous api and and we can estimate the solubility use looking at the heat of fusion
44:00 - 44:30 versus the excipient mass fraction we can estimate the solubility for different excipients and we see so this shows an example of um adipic acid versus glutaric acid and we see that uh the crystallinity um increases and kind of plateaus out beyond the point where the excipient has maximum solubility in the amorphous api we also see that if we measure the glass
44:30 - 45:00 transition temperature of the equivalent composite systems that the glass transition temperature is decreasing and levels out beyond this maximum solubility point uh we've demonstrated this for another drug this is uh salgutamal sulfates where we estimate the amorphous com uh content by dvs dynamic vape absorption analysis and again
45:00 - 45:30 interesting for a range of carboxylic acids it's a glutamic acid that performed best in terms of minimizing amortization and again the minimization of amorphisation kind of comes at the point at or just beyond the maximum solubility of glutaric acid in the amorphous drug so we know that the kind of the key points and i know we're stuck for times there so
45:30 - 46:00 i'm going to wrap up i think just a few more slides and what we moved on to do is look at it just as a screening method where we looked at can we by dsc measure the tg so we want a single tg that's pretty low and can we relate that to selection of excipient and we demonstrated for grizzo fulvin and budesonide that this screening approach can work using a recipient with a low tg
46:00 - 46:30 that has good solubility in the amorphous api so in conclusion then in terms of amorphous materials yes they're a huge benefit to the formulation scientist in terms of their improved solubility and dissolution characteristics there are challenges with respect to the physical instability of the amorphous form um to allow us to harness the advantages we need to
46:30 - 47:00 to be aware of the need to improve the physical instability and amorphous solid dispersions provide an opportunity for us to harness these benefits of the amorphous state um and where the amorphous form is an undesired contaminant of a largely crystalline system there are potential strategies that we can use to overcome this undesirable amorphisation and so with that i'd just like to thank
47:00 - 47:30 all the contributors to the work colleagues postdocs and phd students and the funding agencies and thank you for your intention thank you everybody sir that was a fantastic talk um so if anyone has any questions uh please just put up your hand and and um i can you can turn on your microphone or type it up in the chat uh i might kick off with with one question emery um
47:30 - 48:00 so the to to define your particular amorphous state um dsc really your tg kind of defines what that you have a particular amorphous state so in general do you find with the same if you were to use say the same in your solid dispersions or even in a in a pure drug amorphous state can you guess depending on how you process it do you get can you get a range of different amorphous states with different tgs
48:00 - 48:30 and then with that in mind um you know we always talk about it and you presented a few examples of how maybe during dissolution you get uh the amorphous state converts or transforms to the crystalline state do you ever see it transforming to a different amorphous state um yeah so interesting questions i mean i i think we certainly do see different amorphous states in that there's this polyamorphism
48:30 - 49:00 concept and if you think about the amorphous state you know okay we don't have the three-dimensional long-range order but we do have a level of short-range order so there can be different types of short-range order um so i i guess to answer that first question yes you can have different amorphous states and different um potentially different [Music] levels or different short-range ordering and and subtly different glass transition temperatures and
49:00 - 49:30 the other question in terms of crystallization what was this crystallization and will you get crystallization more do you ever see conversion from one amorphous state to another amorphous state during storage or during dissolution or anything like that i don't know that you get direct conversion at least it's very difficult to see you know but i i think what's more likely to see is that you'll get no i don't think you'll see another
49:30 - 50:00 discreet amorphous state you'll get a more gradual transit transition from one amorphous state to the crystalline state but it won't from one amorphous state to another amorphous state and then lower energy amorphous state no i mean you can get an you know an annealing effect where you can get a um more yeah closer to equilibrium amorphous state but i don't know that you would call that a discrete different to isolate it or yeah yeah
50:00 - 50:30 okay excellent um if anyone has any questions i see a question there from luis um would it be appropriate to name polymorphism for different amorphous states no i mean i don't i i i you know people use this term polyamorphism um which is what we've we've kind of said you know they're different levels of of short-range order but but i think that's very hard to define you know i mean polymorph a polymorph is very easy to
50:30 - 51:00 define and very easy to characterize it's you can't how do you determine that something is a discreetly different level of amorphous nature because it by its nature it's completely disordered right so what makes it disordered in one way compared to another way i don't i don't think so just to follow up on that you know like for i guess it would be a shift in your tg or potentially in solid state anymore if you saw a shift in any peak position
51:00 - 51:30 it might be different yeah but i think the the problem is it's going to be a kind of a continuum right i'd agree yeah it's not going to see one discrete amorphous state and then another discrete amorphous state whereas with crystalline materials they they're very discreet solid state forms but in the case of solid dispersions do you think you could have very discreet amorphous forms when you use a different polymer for example yeah
51:30 - 52:00 yeah absolutely you could have and also with solid dispersions you will you will get this difference between do i have you know a completely intimately mixed polymer drug system or do i have a system where i have polymer rich phase versus api rich phase you know yeah absolutely um i have another question i have loads of questions but i'll just ask this one more then i'll see if anyone else that's in the audience have another question
52:00 - 52:30 like the other way um more and more complex apis are kind of coming through the pipeline in terms of you know higher molecular weights for example things like amphotericin b or just higher molecular weights and what we find molecules that are more difficult to crystallize do you think that with some of these larger more complex still small molecule but they have solubility challenges they've quite a degree of
52:30 - 53:00 um flexibility within the molecular structure do you think that amorphous formulations will play a greater role um in getting these types of molecules to the market and getting them to succeed yeah and i i think we're already seeing that you know i think there are companies that um that have already moved to to as i said earlier be more comfortable in using the amorphous form um and
53:00 - 53:30 molecules that would have been dead in the water previously because they only wanted to consider a crystalline stable physically stable form and they are coming through to later stage development now because of the opportunity provided by amorphous solid dispersions i mean they've been around now for for a couple of decades so it's not necessarily a new technology anymore i think people are more comfortable with it there's still lots
53:30 - 54:00 to be learned about them and you know which is great because we wouldn't have phd students post docs working on them otherwise but um but i think from a commercial product point of view there's um opportunities there that the companies are seeing and that and that's enabling them to bring through more of these large molecule hard-to-handle drugs yeah yep excellent um okay so is there any other questions from anyone in the audience
54:00 - 54:30 oh i think does someone have their hand up there yet so harsh if you want to unmute yourself did you have your hand up yeah yeah yeah so it was a really interesting talk thank you so thank you for that so my question was regarding uh the polymer selection so sometimes like if a particular polymer is stabilizing amorphous form in a solid state but it may fail during the solution state stabilization so is there a way to anticipate
54:30 - 55:00 uh such failures or like can we screen polymers that uh can cause both the kinds of stabilization as in the solid state and the solution stream yeah i mean there are um i have it on another slide but i didn't show that there are kind of you know um selection mate matrices if you like or work our workflows that allow you to choose particular polymers might be better for spray drying versus hot melt
55:00 - 55:30 extrusion and so on particular polymers might have greater benefit in terms of the physical stability solid state versus enhancing solubility in the liquid state and in early stage product development companies will typically spraying a range of polymers both for the physical stability by doing like accelerated stability study and they'll screen the dissolution characteristics or the solubility characteristics so they'll do those in
55:30 - 56:00 tandem and often uh with newer products that are coming through now they won't just depend on a single polymer they'll use a combination of polymers and because you're right you know some are particularly good at keeping it in the amorphous state in the solid dosage form and others are better when it comes to the env situation and enhancing or maintaining that supersaturation and so what i've seen is that now companies are
56:00 - 56:30 looking to use smart combinations of polymers to get benefit in both aspects yeah and that makes sense thank you okay thank you uh so if there's no more questions i see we lost a couple of people just in the last few minutes marie who had lectures at one o'clock a lot of thanks for the great talk um from lots of people so just to to thank
56:30 - 57:00 you again for today really interesting talk and um i think everyone learned a lot and when we struggle to crystallize we might be picking your brains again about some amorphous formulas crystallizing what happens to my whole team then in the ssbc well thank you very much for today all right thanks everybody bye bye