Abstract
Background: Spray drying is a common technique to produce inhalable high-dose dry powder for treating lung infections. However, the particles produced by the technique usually precipitate in an amorphous state which can exhibit hygroscopicity, poor aerosol performance, and low chemical stability. Co-amorphization of a drug with amino acids to prepare drug-amino acid molecular mix has been explored to stabilize the amorphous state of a drug. However, its potential to improve the aerosolization, and chemical stability of spray-dried amorphous particles has not been well-explored. Hence, this work primarily aimed to explore the potential of co-amorphization to prepare highly aerosolizable physically and chemically stable single drug or fixed-dose combination dry powders using a spray dryer.
Methods: Kanamycin and ceftazidime were used as model drugs to assess the influence of co-amorphization of a drug with different non-polar amino acids on aerosol performance. The amino acids (valine, leucine, methionine, phenylalanine, and tryptophan) were selected based on their ability to form co-amorphous systems. The physical and aerosolization stability of the kanamycin-amino acid co-amorphous systems were assessed at 25 °C/<15% relative humidity (RH), 25 °C/53% RH, and 40 °C/75% RH. The influence of amino acid proportion and feed concentration on aerosol performance of such drug-amino acid amorphous composite particles was investigated using the kanamycin-methionine system by varying methionine content from 0–20% and feed concentration from 0.2–0.8%. In addition, with ceftazidime, the influence of co-amorphization on chemical stability in an amorphous state was also assessed. The chemical stability was assessed at 25 °C/<15% RH. For the preparation of fixed dose combination dry powder, the influence of incorporating a second drug into an optimal drug-amino acid co-amorphous spray-dried particle was investigated using ceftazidime-leucine as the model system and roflumilast (5–20%) as the second drug. Potential toxicity of the amino acids, ceftazidime and roflumilast were assessed using alveolar epithelial cell line (A549).
Results: In total, 9 co-amorphous systems (kanamycin-valine, kanamycin-methionine, kanamycin-phenylalanine, kanamycin-tryptophan, ceftazidime-valine, ceftazidime-leucine, ceftazidime-methionine, ceftazidime-phenylalanine, and ceftazidime-tryptophan) were prepared. For the 4 kanamycin-amino acid systems, all amino acids except valine improved the fine particle fraction (FPF) of kanamycin. Kanamycin-methionine offered the highest FPF of 84%. All the formulations were physically stable at 25 °C/<15% RH over 28 days. At 25 °C/ 53% RH, only kanamycin-tryptophan was physically stable. However, it exhibited a decrease in FPF due to moisture sorption. At the high humidity, amino acid crystallized out or showed a change in amorphicity for the other systems. For kanamycin-valine and kanamycin-phenylalanine, the change in solid state was accompanied by a change in particle morphology and/or solid-bridging between particles; hence, the FPF decreased. However, for kanamycin-methionine, crystallization of methionine was not accompanied by a change in morphology or solid-bridging and a stable FPF was observed. Furthermore, the increase in FPF was directly proportional to the methionine content in the formulations. However, the formulation with 6.7% methionine was as effective as the formulation with 20% methionine in maintaining aerosolization stability at 53% RH. For all kanamycin-methionine formulations containing a variable amount of methionine (6.7, 10, or 20% w/w), crystallization of methionine was accompanied by surface enrichment of methionine. The negative influence of the increase in feed concentration on aerosol performance of kanamycin was mitigated with the inclusion of methionine. At 40 °C/75%, components of all the kanamycin-amino acid systems crystallized out and the powders formed fused masses. For the 5 ceftazidime-amino acid systems, all amino acids improved both the FPF and chemical stability of ceftazidime. Ceftazidime-leucine offered the best aerosol performance (FPF = 78%) and ceftazidime-tryptophan offered the best protection by reducing chemical degradation by 51% over 10 weeks. The increase in FPF with the inclusion of amino acid was associated with an increase in surface asperities. Similarly, non-covalent interactions were identified between tryptophan and ceftazidime in the ceftazidime-tryptophan systems. Inclusion of roflumilast into the ceftazidime-leucine system to formulate ceftazidime-roflumilast fixed-dose combination dry powder changed the solid state of leucine from amorphous to crystalline state. In addition, the inclusion of only 5% w/w roflumilast reduced the surface asperity of the particles and decreased the FPF from 75 to 55%. The amino acids, ceftazidime, and roflumilast were non-toxic to respiratory cell line.
Conclusions: Co-amorphization of a drug with amino acids can improve aerosol performance and/or chemical stability of amorphous spray-dried particles. The proportion of amino acid can affect the aerosolization enhancement behavior of the particles. In addition, the physical stability of the co-amorphous system at high humidity does not guarantee aerosolization stability. Therefore, a thorough assessment of both parameters is recommended to optimize formulations. Similarly, the inclusion of a second drug into an optimal drug-amino co-amorphous formulation to prepare fixed-dose combination should be thoroughly investigated as the inclusion can affect the solid state as well as the aerosol performance of the composite particles.