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Reducing PILL Burden: Challenges and solutions for Lowering the pill burden of amorphous spray dried dispersion drug products.

Solid amorphous dispersions can help increase the solubility and dissolution rate of poorly water soluble drug substances (1,2,3,4) Spray dried dispersions (SDDs) are a type of amorphous solid dispersion created by dissolving the active pharmaceutical ingredient (API) and excipient(s) (e.g., polymer) in a common volatile solvent and then atomizing the solution into a stream of hot drying gas. (5,6) As the solvent evaporates from the droplet, the solutes rapidly solidify, trapping the drug substance in an amorphous state within the excipient matrix. To create a drug product, SDD intermediates are incorporated into dosage forms such as tablets or capsules, with immediate release tablets being the most common. (7,8,9)

Design of an SDD drug product is a multivariate optimization targeted to influence a range of characteristics: the desired pharmacokinetic profile in vivo, SDD and drug product stability, manufacturability, decreased cost and patient compliance. (10) To facilitate disintegration and dissolution in gastrointestinal (GI) fluids, maintain physical stability and promote downstream manufacturability, the SDD drug product typically needs to contain a high fraction of excipients, which can result in a large size or number of dosage units, which can dissuade patients from adhering to a drug regimen. Pharmaceutical manufacturers can sometimes minimize pill burden without jeopardizing these factors by using polymers with high glass transition temperatures (Tg) to maintain physical stability, distributing stabilizing polymers across the SDD and drug product to maintain performance and engineering SDD particle size and morphology to facilitate favorable downstream manufacturing.


The tablet mass or capsule shell size and number of dosage units needed to achieve a given active dose can vary widely. For example, the mass of an SDD immediate release tablet depends upon the API loading in the SDD and the SDD loading in the tablet. Typical API loadings in the dispersion range from 10-40%, but can sometimes reach 50% and beyond. Typical SDD loadings in the tablet often range from 40-70%. Figure 1 demonstrates the total tablet mass needed to achieve a 100 mg active dose as a function of the dispersion loading in the tablet and the API loading in the dispersion. Given the typical ranges described above, a total tablet mass of 350-2000 mg would be required to achieve a 100 mg active dose.

The marketed drug product Intelence is an example of an SDD incorporated into a tablet at a 100 mg active dosage strength. (11) Intelence has a total tablet mass of 800 mg and 12.5% API in the final tablet blend. For SDDs incorporated into capsules, the required capsule size is a function of the percentage of drug in the formulation, formulation density, packing properties and compressibility as well as encapsulator type and processing parameters. (12-13)


The desired tablet or capsule size and number of dosage units depends upon many factors, such as dose, indication, age of the targeted population (e.g., adult, pediatric, geriatric), healthy or disease state, desired market image and whether or not the product is targeted for first-to-market or represents a line extension formulation. Pill burden is not always a challenge for SDD drug products. Low-to-moderate dose compounds can often be formulated into tablets or capsules small enough to allow for high patient compliance in a healthy adult population. For example, the marketed drug product Afinitor is an amorphous dispersion formulated in tablets, and despite an API loading of only 2% in the final tablet blend, the low doses of only 5/10 mg allows for a 250/500 mg tablet mass. (14) However, for high dose products, fixed dose combination products and products for pediatric or geriatric populations, for example, pill burden may be a significant challenge.

According to Pharmacircle, (15) 24% of all prescription drug products marketed worldwide have doses of 200 mg or greater, and 56% of drug products indicated for infections have doses of 200 mg or greater. Therefore, it is likely that new amorphous dispersion products indicated for infections may require strategies for limiting pill burden. Of 23 FDA approved amorphous dispersion tablets summarized in several review articles, (7,8,9-16) 70% are products containing single drug substances. Within these products, greater than 30% have maximum dosage strengths of at least 200 mg. Of the fixed dose combination products, greater than 70% have a maximum combined dosage strength of at least 200 mg. This information suggests that a substantial fraction of drug substances requiring solubilization enhancement via amorphization also have high maximum dosage strengths and could potentially be improved upon by second generation products with reduced pill burden.


The addition of polymers into solid amorphous dispersions is a well-established strategy for achieving target pharmacokinetic profiles in GI fluids (17,18,19) and maintaining physical stability of amorphous APIs during manufacturing and storage. (20,21) In most cases, the concentration of API in the SDD exceeds the crystalline solubility of the API in the polymer, leading to a thermodynamic driving force for crystallization. This driving force is due to the positive difference in enthalpy, entropy and free energy between the amorphous and crystalline forms of the API. This excess free energy is what drives nucleation and crystallization. The goal in formulating a dispersion is to create an amorphous, homogeneous SDD and ensure the system is kinetically stabilized at relevant storage temperatures. Achieving this goal at the SDD level is critical, as it is the main determinant of the physical stability of the SDD drug product.

The type of polymer and the ratio of polymer to API chosen can affect SDD physical stability, and should be balanced with performance, chemical stability, manufacturability and cost. Some factors that influence physical stability of the SDD are related to the API (e.g., glass transition temperature (Tg), heat capacity, melting point and heat of fusion), the polymer (number of available hydrogen bond donor and acceptor groups, Tg and molecular mass) and the combination (e.g., diffusion coefficient of the API in the polymer and chemical interactions between the polymer and API that increase the activation energy for nucleation). (22) Water uptake into the SDD during storage can lower the Tg, which can increase the mobility of drug molecules and therefore adversely affect physical stability. (23) Additionally, increasing the API loading in the dispersion can increase the degree of drug supersaturation in the dispersion, leading to a lower Tg of the SDD, since the APITg is often lower than the polymer Tg. When high API loading in the dispersion is desired, it becomes advantageous to select a polymer with a relatively high Tg to reduce API mobility in the dispersion. Another consideration in polymer selection is the number of hydrogen bonding groups. A polymer with a large potential to hydrogen bond will absorb more water, which plasticizes the formulation and reduces physical stability.

Poly(methaciylic acid-co-methyl methacrylate) (PMMAMA), or trade name Eudragit L100, is an example of a polymer ideal for promoting physical stability at high drug loadings, mainly due to its high Tg (191[degrees]C, dry). Figure 3 shows the Tg versus percent relative humidity profiles for an API manufactured in Eudragit L100 at a 60% API loading compared to the same API manufactured in a hydrophobic grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS) at the same loading. Across a relative humidity range of 0-75%, theTg of the Eudragit L100 SDD is at least two-fold that of the HPMCAS SDD. In addition, accelerated stability studies conducted for up to 4 weeks at 40[degrees]C/75% RH showed no detectable crystallization for the Eudragit L100 SDD but did show evidence of crystallization for the HPMCAS SDD via modulated Differential Scanning Calorimetry (mDSC), Scanning Electron Microscopy (SEM) and Powder X-ray Diffraction (PXRD).


Bioperformance evaluation during formulation development hinges on identifying the rate determining step(s) to oral absorption, such as dissolution rate, solubility or membrane transport. The problem statement and formulation strategy can change depending on the physicochemical properties of the API, the target pharmacokinetic profile in vivo, and the current phase of the drug development program. If the API is slow to dissolve or rapidly crystallizes when supersaturated in solution, use of a dispersion polymer in the formulation is typically needed to achieve target oral bioperformance in GI fluids.

The properties of the dispersion polymer can vary widely and allow the formulator the flexibility to select the appropriate polymer based upon the problem statement. Polymers that are neutral (e.g., non-ionizable across the GI pH range) and hydrophilic (high water solubility) such as polyvinyl pyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) are useful for maximizing dissolution rate across the pH range of the GI tract, particularly for highly lipophilic, weakly basic compounds in the low pH environment of the stomach. Weakly acidic enteric polymers, such as PMMAMA (e.g., trade names Eudragit[R] L100 and Eudragit S100) or HPMCAS, are useful for enteric protection (limiting drug release from the formulation in the stomach) or targeted drug delivery as the polymer remains undissolved until it becomes ionized at neutral pH of the intestine.

The fraction of polymer relative to the fraction of API in the SDD chosen to maximize performance also depends upon the physicochemical properties of the API and the target product profile. Generally, a higher fraction of polymer relative to API (i.e. < 40% drug loading) results in improved crystallization inhibition in GI fluids for a rapidly crystallizing API. For a highly lipophilic API, a higher fraction of hydrophilic polymer relative to API generally results in a faster dissolution rate. In turn, the need for a high fraction of polymer relative to API in the SDD results in dilution of the API in the final dosage form. In some cases, distributing performance functionality into the final dosage form rather than relying on a single dispersion polymer in the SDD intermediate can benefit the final formulation in terms of API loading as well as physical stability, without sacrificing performance. Very high Tg polymers such as Eudragit L100 allow the flexibility to push the API loading in the SDD higher than could typically be achieved, while still maintaining a high SDD Tg, and at the same time providing very fast dissolution rate at neutral pH when the polymer becomes fully ionized. Subsequently, to provide maximum supersaturation and sustainment, a concentration sustaining polymer (CSP) such as HPMCAS can be incorporated external to the SDD, but inside the final dosage form. The gain in drug loading achieved by using a dispersion polymer with a much higher Tg compared to, for example, HPMCAS, can sometimes decrease pill burden while still maintaining good performance and stability. This concept is demonstrated in Figure 2 for erlotinib, a weakly basic compound that rapidly crystallizes when supersaturation is induced. In this example, performance was maintained with a high Tg dispersion polymer and external CSP in the tablet. API loading using this architecture was improved two-fold compared to the conventional benchmark formulation where the dispersion polymer acts as the CSP.


Some key factors for facilitating downstream manufacturability (e.g., incorporating SDDs into tablets or capsules) include adequate flow-ability and mechanical properties to meet critical product attributes such as content uniformity, disintegration and dissolution performance, and friability using reasonable compression pressures and throughputs. Generally, there are two methods for downstream processing of SDDs into tablets: direct compression and dry granulation. Direct compression is typically preferred for immediate release tablets to reduce costs by minimizing processing steps, but it requires adequate particle size, density and flow to mitigate potential segregation and poor content uniformity. More commonly for SDDs, dry granulation is used to obtain large, dense granules to minimize these downstream processing risks and to attenuate any changes in SDD properties due to natural variation of the process and raw materials.

The loading of SDD in the tablet formulation is a multifaceted optimization problem that balances desired dose, tablet size, performance, flow and mechanical properties of the blend, to name a few. Selection and amount of tableting excipients (e.g., compression & flow aids, binders, lubricants, disintegrants, and glidants) is based upon achieving these attributes. Increasing the SDD loading in the tablet can negatively affect disintegration due to an increase in the polymer content in the tablet, resulting in gelling or swelling. In addition, depending on the physical properties of the SDD itself, increasing polymer content in the tablet has the potential to increase strain rate dependence (e.g., decreased tabletability at increased manufacturing speeds). (24)

Due to the film forming nature of the dispersion polymer matrix, the SDD mechanical properties and flow can be engineered through the process of spray drying to act as both a tablet filler and active ingredient. Particle size and surface area, wall thickness, and morphology can be tuned through process parameters such as outlet temperature, atomization, and solution viscosity. (25) For example, the particle deformation mechanism and available contact areas of a single SDD formulation can be altered, varying tablet strength and porosity as illustrated with polyvinyl pyrrolidone vinyl acetate (PVP-VA) SDDs in Figure 4. Varying SDD mechanical properties in this way could lead to a reduction in the fraction of compression aids needed in the formulation, resulting in a reduced pill burden risk. In addition, high density, large particles can also be engineered to reduce segregation and content uniformity risks, potentially removing the need for dry granulation. For SDD in capsule manufacturing, the maximum SDD loading in the final dosage form can be improved by increasing density and flow by particle engineering, dry granulation or increasing flow by dry particle coating with glidants. (13)


Design of an SDD drug product must balance important factors such as performance, stability and manufacturability. Achievement of performance and stability of SDD drug products often hinges on including a polymer in the formulation to stabilize amorphous drug in intestinal fluids and during manufacturing and storage. Addition of the polymer can lead to significant dilution of the API in the final drug product, causing a high pill burden, particularly when the desired dosage strength is in the hundreds of milligrams. Strategies such as using high Tg polymers to maintain physical stability of the SDD at high drug loading, distributing performance functionality across the SDD and drug product to enable high SDD drug loading for rapidly-crystallizing drug substances, and engineering SDD particles to aid downstream manufacturability, are all strategies for enhancing SDD drug products while decreasing pill burden.

For a full list of references please visit the online version of this article at

Deanna Mudie, Principal Scientist R&D

Aaron Stewart, Sr. Scientist R&D

Stephanie Buchanan, Sr. Scientist R&D

Alyssa Ekdahl, Engineer R&D

Lonza Pharma & Biotech

Caption: Figure 1. Total tablet mass to achieve a 100 mg active dose as a function of dispersion (e.g., SDD) loading in the tablet and API loading in the dispersion (e.g., SDD).

Caption: Figure 2: Dissolution results from a simulated gastric fluid (SGF)/simulated intestinal fluid (SIF) transfer test comparing 1) a high loaded dosage form "HLDF" new architecture formulation (33% w/w API, 300 mg total tablet mass) comprising a high Tg dispersion polymer with a CSP external to the SDD but in the tablet to 2) a traditional benchmark formulation at a lower drug loading (17% w/w API, 575 mg total tablet mass). Both tablet formulations contain the same active dose.

Conditions: Dissolution for 30 min in simulated gastric fluid (0.01 N HCI, pH 2) at an erlotinib concentration of 500 pg/ mL. Dissolution in simulated intestinal fluid (6.7 mM sodium taurocholate in phosphate buffer, pH 6.5) for the next 90 min after a 1:1 dilution of SGF:SIF to a final erlotinib concentration of 250 [micro]g/mL. Data collected in duplicate.

Caption: Figure 3. Tg versus %RH for an API at a 60% (w/w) loading in either PMMAMA (Eudragit[R] L100, Evonik) or HPMCAS (AQOAT[R] hydrophobic grade, Shin-Etsu) as measured via mDSC.

Caption: Figure 4. Comparability profiles of four different 100% PVP-VA SDDs ("A", "B", "C" and "as received", center) produced using different spray drying processing conditions and SEM micrographs of a cross section of compacts of SDDs "A" and "B" compressed at 80MPa (bottom) and 220MPa (top). A programmable stress and strain compaction instrument using a 5mm/sec linear saw-tooth strain rate profile was used to generate the compactibility profiles of the SDDs. External lubrication was applied to the die and tooling prior to each compression (25)
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Author:Mudie, Deanna; Stewart, Aaron, Sr.; Buchanan, Stephanie; Ekdahl, Alyssa; Lonza
Publication:Contract Pharma
Date:Jan 1, 2019
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