Feasibility of Spray Dried Dispersion (SDD) Based Low Dose Tablet Formulation

                                                                                                        

BACKGROUND

The design and development of low-dose solid drug products presents a unique set of challenges during drug product development.  The key concern with a low-dose product is achieving and maintaining acceptable content uniformity of the therapeutic active.   In addition, frequently there is a need to utilize enabling technologies to increase bioavailability of poorly soluble drugs.  Rendering the active therapeutic moiety to be in an ‘amorphous state' is a promising approach to obtain a material with high kinetic solubility.  In pharmaceutical industry, the bulk amorphous dispersions are often manufactured using the spray drying technology.  The process involves dissolving the active drug and polymeric carrier(s) in a solvent system, followed by evaporating the solvent in a spray dryer.  Notably, the spray dried materials often have physical properties (size, shape and flow) that are different than those of traditional solid dose excipients.

This work assesses the feasibility of developing a low dose SDD formulation with a representative material,  composed of  30% API and 70% hydoxypropyl-methylcellulose acetyl succinate (HPMC-AS) polymer.  To support clinical development a wide dose range is often necessary; it is preferable to use a common SDD (same drug loading) to ensure consistent performance and to minimize complexity with regard to SDD process development.   Hence the provision of low dose tablets, for example as low as 0.1mg, using very small quantities of SDD, necessitates high assurance of content uniformity.  The manufacturing process described in this work follows a dry granulation process which was selected to provide for acceptable physical stability, and to reduce the risk of segregation and poor content uniformity.

Traditional models for predicting content uniformity (Rohrs et al.) based on mean particle size and distribution skew suggest that the risk of content uniformity failure for typical SDD material (e.g. D50 40µm) in a 1mg formulation is low (P<0.1%), whilst for a 0.1mg tablet the risk of failure rises particularly as the size distribution becomes skewed, for D90/D50 ratio >2, P failure >8%.  The feasibility of using low dose SDD based formulations therefore presents unique challenges which to date have not been fully explored.

 

METHODS

Tablets were manufactured at a 10 kg scale (0.1 mg and 1.0 mg potency) using 0.33 and 3.33% SDD (SDD contained 30% w/w active in its amorphous state).  The SDD and excipients (microcrystalline cellulose, anhydrous lactose, croscarmellose sodium and magnesium stearate) were mixed in a low shear blender, followed by co-milling and further blending, and subsequently roller compacted (Alexanderwerk WP120).  The resultant ribbons were milled, lubricated and compressed on a rotary tablet machine to a target press weight of 100 mg.

During compression tablets were sampled over five regular intervals and analyzed for content uniformity (total 5 x 10 tablets).  Each final blend was riffled and separated into sieve fractions and the active content determined using HPLC for each fraction (>425µm, 180-425 µm, 63-180 µm, <63 µm).  A modified Jenike & Johanson segregation test was also employed to evaluate segregation potential.  The test used four cycles through a standard hopper design and a 1.8m gravity drop, six 100 mg samples were analyzed for content at different segments of the discharged blend.   The physical distribution of SDD in the formulated tablet was also evaluated by FTIR imaging  (Thermo Raman DXR). SDD particle size was determined using a Malvern Morphologi G3 and the morphology was confirmed by SEM.

 

RESULTS

SDD particles produced from the representative spray process were determined to have a mean D50 and D90 of approximately 30-40 µm and 50-60µm, respectively, with a characteristic collapsed sphere morphology.  The content uniformity for low dose tablets gave consistently low variation throughout compression , for example the %RSD  for 0.1mg tablets remained between 1.5%- 2.4%  for all five segments.

The sieve cut potency data, however, showed an uneven distribution of active through the particle size range, with fines (<63um) being super-potent and at least 1.6x nominal content.  The data corroborated with the J&J segregation test results which showed an elevated RSD and potency range for the samples analyzed; suggesting a risk for segregation of the final blends on scale up.

 

Tablet Strength	Mean %RSD Tablet (n=50 )	J&J Segregation Results
		%RSD	Risk*	Potency range (%)	Risk*
0.1 mg	1.97	5.5	Medium	23.6	High
1 mg	1.8	5.5	Medium	21.6	High

                                        *Based on the proposed segregation risk classification system, Shah et. al.

 

CONCLUSIONS

Although the theoretical content uniformity model predicted borderline uniformity for the 0.1mg strength product, the experimental data from the manufacture of low dose SDD tablets at a ~10kg scale indicated good dose uniformity is feasible.  The content uniformity model assumes that particles are solid, however for hollow or collapsed SDD structures the particles will contain less mass per particle than expected.  Therefore, the risk of content uniformity failure will be lower than predicted, with the risk decreasing with lower solid volume fraction (wall thickness).  Acceptable uniformity was supported by FTIR imaging showing even SDD distribution on the tablet surface.  The granule sieve cut potency and the J&J segregation test results indicate that the risk for segregation remains, and needs to be addressed during process scale-up and bulk transfer operations.

ACKNOWLEDGEMENT

The technical contributions by the Bend Research Inc. team in developing the Spray Dried Dispersions are hereby acknowledged.

 

REFERENCES

-        Rohrs, B.R., Amidon, G.E., Meury, R.H., Secreast, P.J., King, H.M., Skoug, C.J. (2006). Particle size limits to meet USP content uniformity criteria for tablets and capsules.  J. Pharm. Sci. 95(5), 1049–1059.

 

-        Shah, K.R et al. (2007)' Assessment of Segregation Potential of Powder Blends', The Pharmaceutical development and technology', Informa healthcare, Volume 12, pp 457-462.