Spray drying formulation of amorphous solid dispersions
Abhishek Singh1, Guy Van den Mooter1*
1 Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
*Corresponding author:
Address- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven; Campus Gasthuisberg O+N2; Herestraat 49 b921, 3000 Leuven; BELGIUM
Tel.: +32 16 330 304 fax: +32 16 330 305 Mobile: +32 473 356 132
e-mail:
Graphical Abstract
Abstract
Spray drying is a well-established manufacturing technique which can be used to formulate amorphous solid dispersions (ASD) which is an effective strategy to deliver poorly water soluble drugs (PWSD). However, the inherently complex nature of the spray drying process coupled with specific characteristics of ASD makes it an interesting area to explore. Numerous diverse factors interact in an inter-dependent manner to determine the final product properties. This review discusses the basic background of ASD, various formulation and process variables influencing the critical quality attributes (CQA) of the ASD and aspects of downstream processing. Also various aspects of spray drying such as instrumentation, thermodynamics, drying kinetics, particle formation process and scale-up challenges are included. Recent advances in the spray-based drying techniques are mentioned along with some future avenues where major research thrust is needed.
Keywords
Amorphous solid dispersions, Spray drying, Poorly water soluble drugs, Mollier diagram, Drying kinetics, Scale-up, Downstream processing, Process parameters, Carrier, Electrospraying
Abbreviations
AGU- Anhydro-D-glucopyranose units
API- Active pharmaceutical ingredient
ASD- Amorphous solid dispersions
ATR-FTIR- Attenuated total reflectance Fourier Transform Infrared Spectroscopy
BCS- Biopharmaceutics classification system
CAP- Cellulose Acetate Phthalate
CAAdP- Cellulose acetate adipate propionate
CMC- Carboxymethyl cellulose
CMCAB- Carboxymethylcellulose acetate butyrate
Compritol 888 ATO- Glyceryl dibehenate
CQA- Critical quality attributes
DCM- Dichloromethane
DMA- N,N-dimethylacrylamide
DOE- Design of experiments
EC- Ethylcellulose
EHEC- Ethylhydroxyethyl cellulose
Gelucire- Lauroyl polyoxyl-32 glycerides
GI- Gastrointestinal
Inutec SP1- Inulin Lauryl Carbamate
HEC- Hydroxyethyl cellulose
HME- Hot melt extrusion
HPC- Hydroxypropyl cellulose
HPCDS- Hypulcon pulse combustion dryer system
HPMC- Hydroxypropyl methylcellulose
HPMC-AS- Hydroxypropyl methylcellulose acetate succinate
HPMC-P- Hydroxypropyl methylcellulose phthalate
Kollicoat IR- Polyvinyl alcohol-polyethylene glycol graft copolymer
MC- Methylcellulose
MCC- Microcrystalline cellulose
Myrj 52- Polyoxyl 40 Stearate
NaCMC- Sodiumcarboxymethyl cellulose
NIR- Near infra-red
PAT- Process analytical tools
PCSD- Pulse combustion spray dryer
PDMA- Poly-dimethylacrylamide
P(DMA-grad-MAG)- Poly (N,N,-dimethylacrylamide-grad-methacrylamido glucopyranose)
PEG- Polyethylene glycol
PEP- Poly(ethylene-alt-propylene)
PEP-PDMA- Diblock copolymer of DMA and PEP
PHPMA- Poly[N-(2-hydroxypropyl)methacrylate]
Poloxamer- Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)
PVP- Poly(vinylpyrrolidone)
PVP VA64- Poly(1-vinylpyrrolidone-co-vinyl acetate)
PWSD- Poorly water soluble drugs
QbD- Quality by design
QTPP- Quality target product profile
SCM- Supercritical methods
SLS- Sodium lauryl sulphate
Soluplus- Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer
Sucroester 15- Sucrose monopalmitate
THF- Tetrahydrofuran
Tg- Glass transition temperature
Vitamin E TPGS- D-α-tocopheryl polyethylene glycol 1000 succinate
Table of Contents
1. Introduction
2. Amorphous solid dispersions (ASD)
3. Spray drying process
4. Thermodynamics of spray drying
4.1 Drying kinetics
4.2 Mollier diagram
5. Particle formation process and the effect of the process parameters
5.1 Feed variables
5.1.1 Solvent system
5.1.2 Influence of solute components in feed solution
5.1.3 Feed solution stability
5.2 Process parameters
5.2.1 Feed flow rate
5.2.2 Inlet and outlet temperature
5.2.3 Atomization and drying gas type and flow rate
5.2.4 Types of atomization device
6. Carriers for spray dried solid dispersion formulations
6.1 Poly (ethylene oxide) polymers and derivatives
6.2 Cellulosic Derivatives
6.3 Vinyl Polymers
7. Multi-component solid dispersions
8. Influence of preparation method
9. Recent advances
9.1 Electrospraying
9.2 Pulse combustion spray dryer (PCSD)
10. Scale-up challenges
11. Quality by design (QbD) and process analytical tools (PAT) in spray drying
12. Downstream processing and product development
13. Future outlook
14. References
1. Introduction
As we enter into the latter half of the current decade, the paradigm of solubility challenges faced by formulation scientists remains largely unchanged. Many of the drug molecules can be categorized under Biopharmaceutics classification system (BCS) class 2 or 4 (Figure 1) [1]. The problem is a difficult one to overcome because of multifaceted factors driving it. The use of non-aqueous (or solvent mixture) based media for screening and purification purposes in high throughput screening tend to give hits with higher molecular weight and lipophilicity [2, 3]. The quest for identification and targeting of kinase pathways, ion channels, nuclear receptors and protein-protein interactions with potent and selective agents is also motivating the choice towards lipophilic compounds [4, 5]. The presence of many low solubility compounds in the drug discovery pipeline is not good for any stakeholder of the drug development process due to high fall-out rate and associated development costs. Apart from chemistry based strategies to improve solubility, onus is on formulation scientists to provide enabling drug delivery strategies for such candidates.
Figure 1: Biopharmaceutics classification system and various approaches to overcome solubility and permeability challenges. (Adapted from [6, 7])
For a compound to reach to its target site, it should first be dissolved in the gastrointestinal (GI) fluid (in most of the cases) [7]. The rate at which this happens is given by the Nernst Brunner equation [8].
dCdt=SD (Cs-Ct)Vh …..Eq.1
Here, dC/dt- dissolution rate of the drug, S- surface area of the dissolving surface, D- Diffusion coefficient of the drug, Cs- Saturation solubility, Ct- concentration at time t, V- volume of dissolution medium and h is the thickness of the diffusion layer surrounding the dissolving particle. Diffusion coefficient of the drug and dissolution medium volume are the factors which cannot be significantly modified in vivo. Thus, the enabling strategies focus on altering solubility and/or surface area.
Amorphization is an approach wherein the solid state form of the drug is changed from crystalline to amorphous. The rationale behind this approach can be understood by the following equation [9].
∆GT° Amorphous,Crystalline=-RTlnσTAmorphousσTCrystalline …..Eq.2
Here, ∆GT° Amorphous,Crystalline is the energy difference between the crystalline and the amorphous state, R is the gas constant, T is the absolute temperature of concern and σTAmorphousσTCrystalline is the solubility ratio of the two forms. It follows from equation 2 that the amorphous form has a higher theoretical solubility as compared to the crystalline form due to its excess thermodynamic properties (Figure 2). In simple terms, in the amorphous state there is no energy requirement to break the crystal lattice structure so that the drug molecules can interact with solvent molecules through intermolecular interactions and become solubilized. But the excess thermodynamics properties of amorphous forms also result in their tendency to crystallize thereby negating the solubility advantage. ASD can be considered as a potential solution to this issue.
Figure 2: Thermodynamic descriptor-temperature diagram for the various states of a drug.
As the crystalline drug is heated, the thermal energy breaks the crystal lattice structure and at melting point (Tm) the drug gets converted into liquid state. To generate amorphous state, the liquid should be cooled at a sufficiently fast rate. This results in conversion of liquid to supercooled liquid state and subsequently the system falls out of the equilibrium at the glass transition temperature (Tg). For certain drugs such as itraconazole, formation of mesophase is observed. Tk is the Kauzmann temperature which is a hypothetical temperature at which the entropy of the supercooled liquid becomes equal to that of crystal. Spray drying process is also similar to quenching, as the time scale in which droplet to particle conversion takes place is really small and in ideal cases does not allow crystallization. (Adapted from [10])
2. Amorphous solid dispersions (ASD)
ASD consist of drug molecules dispersed in amorphous polymeric carriers. The drug stabilization is a consequence of factors such as intermolecular interactions, antiplasticization effect exerted by the polymer, physical barriers to the crystallization process (local viscosity) and the reduction in chemical potential of the drug [11]. The role of the polymeric carrier is not limited to the stabilization but also mechanisms responsible for improved dissolution rate and absorption. Hydrophilic carriers such as Poly(vinylpyrrolidone) (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) and hydroxypropyl methylcellulose (HPMC) are highly water-soluble and enhance water uptake into the solid dispersion matrix. Carriers also play a crucial role in maintaining supersaturation and precipitation inhibition in vivo which is widely accepted as critical in improving solubility in the GI tract [12]. Other mechanisms responsible for improved solubility are reduced particle size resulting in increased surface area [13, 14]. In ideal case, i.e., molecular dispersion, the surface area available for dissolution is the maximum since the drug size is reduced to (almost) a single molecule. On several occasions this is not the case and the active pharmaceutical ingredient (API) distribution within the carrier matrix becomes inhomogeneous leading to drug-rich and polymer-rich regions. Since drug polymer miscibility is crucial for solid dispersions stabilization, phase separation can promote API crystallization [15-17]. Therefore, every effort should be made to produce miscible solid dispersions systems and protect them from drivers of phase separation such as high temperature, humidity and mechanical stress [13, 18, 19].
Amorphous to crystalline transition is a thermodynamically driven phenomenon due to lower free energy of the crystalline state and is bound to happen at a certain point of time (the time-scales involved can be really long in absence of external stimuli). But for crystalline to amorphous transition, external energy needs to be imparted to the system. Mechanical activation such as milling can generate amorphous forms [20]. Another way is to either dissolve in a solvent or melt the crystal form to break the crystal lattice structure. The cooling of the API from the molten state (Hot melt extrusion (HME)) or rapid solvent evaporation (Spray drying) from the dissolved state leads to amorphous forms [13]. In this review focus will be on the spray drying. The readers can refer to excellent overviews by Thiry et al. [21], Shah et al. [22], Crowley et al. [23] and Li et al. [24] for further information about HME.
3. Spray drying process
Spray drying is an energy intensive, continuous and scalable drying process [25, 26]. The process can generate nano to micron size particles that have a narrow distribution in a very short time-frame. For the context of this review, spray dryer equipment can be viewed as solid state transforming reactors where the crystalline starting material is converted into amorphous product. The first patent of spray drying process is more than 140 year old wherein it was described as a process for simultaneously atomizing and desiccating fluid and solid substances. The process was meant for exhausting moisture and to prevent destructive chemical change [27]. Historically, the spray drying process has been most extensively used in food and chemical industry. However, its use quickly expanded to other industries such as cosmetics, fabrics and electronics. The first foray of this technique in the pharmaceutical field was for the manufacture of pure API. From there on it has been used ever increasingly for various specialized applications such as microcapsules, controlled release particles, composite microparticles, nanoparticles, and liposomes [28].
The spray drying process sequentially involves several steps involving various components (1-6) as shown in figure 3. Firstly, the feed solution/suspension is pumped into the drying chamber through a nozzle (components 1, 2 and 3). During exit from the nozzle tip the droplets are atomized and come in contact with the drying fluid i.e. hot gas (often air) inside the drying chamber (component 4). The residence time inside the drying chamber depends on the process parameters and the equipment dimensions and may typically last for a few milliseconds. During the transit through the drying chamber energy-mass transfer takes place at the dynamic droplet surface. Finally, the dried material is separated from the drying medium using a cyclone (component 5) and is collected in a collection device (component 6). The exhaust gases are filtered via HEPA filters (component 7). To accomplish the abovementioned steps, various hardware configurations can be used as described below.
Figure 3: Spray drying set-up
Typical spray-drying system consists of various components. Component choice and their operating parameters have crucial influence on the process output. Few of these aspects are listed below the components (1-7).
The choice of the feed pump used depends on the viscosity of the feed material and the type of atomizer system used [26]. Low pressure pumps are desirable for rotary atomizers or bi-fluid nozzles. Pressure nozzles necessitate the use of high pressure pumps. Various atomizer designs are available and use different kinds of forces input to obtain fine droplets [29]. Atomizers can be either rotary, hydraulic (pressure), pneumatic or ultrasonic nozzles. In rotary atomizers, centrifugal force results in breaking down of the liquid stream into small droplets. Modification in the rotary atomizers such as straight or curved grooves provide opportunities for particle engineering [26, 30]. When using this atomization set-up care should be taken to use drying chamber of sufficient diameter. Material adhesion to the drying chamber walls can be a limiting factor for its use for expensive drugs. Bi-fluid or multi-fluid nozzles utilize the pressure energy and can be used with narrow chambers. In pneumatic nozzles kinetic energy of the compressed carrier gas is transferred to the liquid surface at a central collision point causing droplet formation. Ultrasonic nozzles use vibrational energy for atomization but still find limited use in industrial settings due to their low throughput (<50 ml/min) [31]. The vibrational energy is produced by the application of a high frequency electric signal to the two electrodes placed between the piezoelectric transducers [29]. The vibrational motion is transferred and amplified by a titanium nozzle tip. Variations in the construction and operating conditions of these established designs enables to control the particle size distribution and density.
The atomized droplets encounter the drying air in the drying chamber which commonly have a height to diameter ratio of 5:1 (tall) or 2:1 (small) chambers. The air-droplet contact system can be of cocurrent, counter-current or mixed flow type. Cocurrent contact system is most widely employed for pharmaceutical purposes [32]. The droplet size distribution generated by the atomization set-up determines the residence time needed in the chamber and its dimensions as well [33]. The nature of the gas flow (turbulent or laminar) will also have a bearing on the residence time of the droplet, and final product moisture content. Of particular importance for spray drying of amorphous systems is the need for strict inter-batch control of the temperature and humidity of the drying air.