2. Direct Compression of Spray-Dried APIs

Spray drying has been particularly important for enhancing the compression of poorly compressible high-dose drugs. Although the majority of the studies report combinations of drugs with auxiliaries, there are some studies reporting spray drying of a solution of drug without auxiliaries, aiming at compression improvement via changes in the solid state, particle size or shape. The main investigations of drugs spray-dried alone or co-spray dried with excipients are summarized in Table 1.

Di Martino et al. ^[14] [34] spray dried acetazolamide from ammonia solutions. The obtained powder was composed of a mixture of polymorphs I and II. On the other hand, compression of the respective pure polymorphs, obtained by crystallization from solution, was not possible, giving capped tablets even at high compression pressures. This was explained by the remarkable improvement of particle rearrangement in the initial stage of compression of the spray-dried polymorphs due to the spherical shape and minor wrinkledness of the particles.

Paluch et al. ^[15] [35] obtained nanocrystalline microparticles of the poorly compactable chlorothiazide by spray drying a drug solution in water/acetone mixture. Tablets compacted from the obtained nanocrystalline microparticles (Figure 4) had remarkably higher tensile strengths than those from micronized chlorothiazide raw material. In another study from the same group, the compression behavior of several solid forms of chlorothiazide sodium and potassium salts were evaluated. The results proved the superior tabletability of the spray-dried microparticles of both salts that were composed of primary nanoparticles, which offered a larger interparticle contact area during the compaction stage [36]^[16].

Figure 4. SEM images of spray dried chorothiazide nanocrystalline microparticles (A) and raw material (B). From reference [35] ^[15] with permission.

3. Direct Compression of Co-Spray Dried APIs with Excipients

The majority of spray drying applications of drugs involve co-processing with excipients. The presence of the excipients favorably modifies the solid-state crystalline properties and may exercise some binding effect as well. The most commonly investigated excipients are carbohydrates and polymers.

The influence of different carbohydrates on spray drying processability and tableting-related properties (flowability, compactability and hygroscopicity) of spray-dried high-dose drugs has been investigated in a series of published papers [37,38,39,40]^{[17][18][19][20]}. Spray drying of binary and ternary paracetamol-excipient mixtures demonstrated the efficiency of three carbohydrates to improve the physical properties and compactability of this high-elastic relaxation drug. Mannitol and maltodextrin enhanced compactability, while erythritol increased powder density and flowability [37]^[17]. A D-optimal mixture design was employed to evaluate the effects of the three carbohydrates in co spray-dried mixtures. The composition containing 20.9% w/w erythritol, 13.9% w/w maltodextrin and 11.6% w/w mannitol was found optimal regarding powder flow, mechanical strength and disintegration of paracetamol tablets [38]^[18]. In a further study by the same research group, optimization of processing parameters was sought out to obtain RTC mixtures. A mixture of paracetamol with carbohydrates (erythritol, maltodextrin, mannitol), disintegrant (crospovidone), glidant (colloidal silica) and surfactant (polysorbate 80) was co-spray dried. Inlet and outlet air temperatures were found to affect the median particle size, moisture content and flowability. However, regression models for the effect of processing parameters on tablet hardness, friability and disintegration time were not statistically acceptable [39]^[19]. The combination of erythritol, maltodextrin, mannitol, crospovidone, colloidal silica and polysorbate 80 considerably improved the compactability of paracetamol, ibuprofen and cimetidine via co-spray drying in a lab-scale apparatus. Furthermore, high contents of paracetamol (70% w/w) and ibuprofen (75% w/w) were successfully loaded using a production scale spray-drier [40]^[20].

McDonagh et al. ^[21] [41] investigated the role of the soluble fraction of paracetamol and α-lactose monohydrate on the tableting of their crystallo-co-spray dried agglomerates. Different inlet feed solvent compositions were employed to modify the soluble fraction of lactose in the inlet feed. It was found that an increase in the soluble fraction of lactose resulted in greater mixing in the final spray-dried product and greater improvement in compressibility and tabletability [41]^[21].

Polymers with good capability to act concomitantly as binders and crystallinity modifiers are also interesting additives for co-spray drying. They offer the advantage of being used at lower percentage than low-molecular-weight carbohydrates (Table 1) and thus to avoid enlargement of tablet volume of high-dose drugs. Joshi et al. ^[22] [42] prepared amorphous celecoxib and celecoxib-PVP-meglumine ternary mixture by spray drying and compared their compaction behavior with crystalline celecoxib. They found that tablets formed from ternary mixture gave higher tensile strength in comparison with amorphous or crystalline celecoxib. Also, pressure-induced devitrification that inhibited direct compaction of the amorphous celecoxib occurred to a lesser extent in the ternary mixture, thus making it suitable for direct compaction.

Al-Zoubi et al. ^[23] [43] co-spray dried naproxen and naproxen sodium with HPMC seeking out enhancement of compression behavior. Co-processing resulted in reduced crystallinity of naproxen and higher dihydrate content of naproxen sodium. When mixed with suitable processing aids, the co-spray dried powders formed tablets with superior mechanical properties compared to unprocessed or spray-dried alone drug powders.

Chinta et al. ^[24] [44] investigated co-spray drying aqueous acidic solutions of propranolol HCl with chitosan and lactose. Three chitosan grades (low-, medium-, and high-molecular-weight) were evaluated. The spray-dried agglomerates prepared with lactose and chitosan showed excellent flow and were suitable for tableting.

Rathod et al. ^[25] [45] co-processed cefuroxime axetil with chitosan chlorhydrate and mannitol by co-spray drying 5% slurry of drug and carriers at 1:1 drug:excipient ratio in isopropanol. They employed a full factorial design to optimize mannitol:chitosan chlorhydrate ratio and inlet air temperature as independent variables. Analysis of the results using the Kawakita and Heckel models revealed that the batch produced from the optimized conditions had better compressibility than the physical mixture.

Vanhoorne et al. ^[26] [46] co-spray dried paracetamol with mannitol and PVP. Compaction properties of the co-spray dried powders were compared to physical mixtures for compositions containing 75% paracetamol, 20–25% spray-dried mannitol, and 0–5% PVP. Mixtures of co-spray dried paracetamol with 5% PVP and 20% mannitol produced tablets with higher tensile strength than the corresponding physical mixtures at all applied compressions pressures (34–229 MPa). The improvement of mechanical strength by co-spray drying was attributed to the coating of paracetamol crystals with δ mannitol and PVP.

Metformin HCl is a problematic drug for DC processing due to poor compactability and high administered dose (500–1000 mg). Barot et al. ^[27] [47] co-spray dried aqueous solutions of PVP K30 (0–3% w/v) with metformin HCl in an attempt to develop a directly compressible grade. They found that metformin HCl co-spray dried with 2% PVP K30 showed excellent flowability and compressibility as well. Further investigation was sought out by Al-Zoubi et al. [48]^[28], who compared five hydrophilic polymers (HPMC, PVP, copovidone, sodium alginate and sodium carmellose) regarding their ability to enhance the compression behavior of metformin HCl. Co-spray drying with the polymers resulted in increased amorphous drug content associated with increased deformability and reduced ejectability. A significant correlation was found between compaction work and relative crystallinity (p = 0.042), which confirmed the importance of crystalline to amorphous conversion on the deformability and particle bonding mechanisms. However, compactability and tabletability of metformin HCl were improved only by co-spray drying with the anionic sodium alginate and sodium carmellose polymers that could make ionic interactions with the positively charged ammonium of the drug. [48]^[28].

The above results demonstrate the ability of spray drying to convert the crystalline state of the drug to amorphous, which improves interactivity, enhances plasticity and hence deformability and contact area. Additionally, they demonstrate the drug’s ability in the spray-dried particulate form to retain chemical bonds with the excipient formed during spray drying and thus enable modification and improvement of the mechanical properties. Furthermore, the spray-dried particles may present higher polymer concentration at the surface due to the rapidness of the drying process, enhancing bond formation during tableting. Therefore, all the aforementioned mechanisms should be considered when selecting polymers for co-spray drying with the view of tableting improvement.

Honick et al. ^[29] [49] co-spray dried hypromellose acetate succinate (HPMCAS) with itraconazole from organic solutions. They showed that the compacts from solid dispersions (SDDs) had a higher elastic recovery and much greater tendency to laminate, particularly at higher compression speeds, in comparison with physical mixtures. However, the intact compacts from SDDs tended to have higher mechanical strength than those produced from physical mixtures, probably due to the smaller particle size of the SDDs.