Issue link: http://www.e-digitaleditions.com/i/552614
Inhalation AUGUST 2015 9 Water content analyses were performed on a coulomet- ric Karl Fischer (KF) oven set to 150°C with a Metrohm 774 oven and sample processor and a Metrohm 851 (Riverview, FL, US) Titrando. Fluka (Seelze, Germany) 34739 Hydranal Coulomat AG oven solvent was used. Data was evaluated by using the Tiamo 2.2 analysis. Standards and samples were prepared at <10% relative humidity (RH) and ambient temperatures with approx- imately 10-50 mg of powder. A minimum of three repli- cates were performed for analysis. A Bruker (Billerica, MA, US) AXS XRPD X-ray diffrac- tometer with a positional auto sampler arm was used to analyze the physical state properties of the spray dried powders. Samples were loaded onto zero-background holder (ZBH) sample cups with single-crystal silicon sample surfaces. Samples were exposed to the ambient environment and a static bar/gun was used to reduce sta- tic within the sample. Approximately 10-20 mg of sam- ple was added to the center of a ZBH cup using a small spatula. Samples were flattened on the ZBH sample sur- face using a clean glass microscope slide. A clear cover was placed on top of the sample cup. Modulating differential scanning calorimetry (mDSC) analysis was used to identify any glass transition temper- atures (Tg), crystallization temperatures (Tc), or melt temperatures (Tm) for the samples. Samples were scanned over a set temperature range and all three types of events may not have been observed over the scanned range. A TA Q2000 mDSC instrument (New Castle, DE, US) was used and individual scans were evaluated by TA Universal analysis. Samples were prepared at <10% RH and ambient temperatures in a Tzero alu- minum pan with a 1-10 mg sample size. Samples were scanned from -60°C to 200°C using settings described below. The size 3 hydroxypropyl methylcellulose (HPMC) capsules used in this study were transparent DPI grade Capsugel Vcaps (Morristown NJ, US), which have shown low powder retention and minimal-to-no impact on particle quality during stability studies. 4 Amorphous spray dried powders are fairly hygroscopic; therefore, in order to maintain physical stability during storage, they require containment in a low relative humidity environ- ment—oftentimes less than 10% RH. Vcaps are physi- cally stable and maintain integrity under low RH storage conditions and have shown consistent handling and fill- ing in a Capsugel Xcelodose system contained in a low RH environment, which was used in this program. 5 Aerosol evaluation was performed to confirm that manu- factured spray dried powder could be delivered in the res- pirable range. Capsules filled with either 5 mg, 10 mg or 20 mg of spray dried powder were placed in a low resis- tance Plastiape monodose device RS01 (#239700001AB) (Milan, Italy) and actuated through a Next Generation Impactor (NGI, Copley Scientific, Nottingham, UK) for aerosol evaluation. The NGI was actuated for 4 seconds at 60 L/min (4 L total volume) during these studies and albuterol distribution was determined using UV absorbance at 276 nm after the API had been solubilized in water. Emitted fractions (EF) from capsule and device, mass median aerodynamic diameter (MMAD), geomet- ric standard deviation (GSD), and fine particle fractions (FPF) below 5 microns were calculated. A minimum of three replicates were performed per formulation/fill load combination. Post-actuation visual inspection confirmed the capsule retained integrity and the puncture flap was still attached. Results Product concept, technology selection and develop- ment integration During spray drying, a solution or suspension of API and excipients is atomized, which creates droplets that are rapidly dried and converted into solid particles inside a chamber and collected via cyclone. The resultant com- position of spray dry manufactured particles is the same molar ratio of API and excipients as existed in solution or suspension prior to atomization, but without nearly as much of the solvent involved. Considerations during spray drying include the following: 1. solvent(s) being used; 2. API type and concentration; 3. excipient type and concentration; 4. drying conditions; 5. manufactur- ing scale; 6. nozzle type; and 7. feed rate and temperature profile within the drying chamber, as these primary fac- tors impact the character, quality and yield of the manu- factured powder. 6 Often the first step in the spray dry process focuses on the creation of a stable solution or suspension, i.e., a solution or suspension that behaves well enough to enable spray dry manufacture before precipitation or destabilization of the API. In order to make the stable solvent/API/excipi- ent mixture, it is critical to understand the organic and aqueous solubility (or the lack thereof) of drug com- pounds and excipients in question. Matching, or better yet, understanding API and excipients' solubility is important for defining the final state of the API and excipients in the dry state. The physical state of these components of the formulation directly impacts physical aspects of interest to a drug formulator, such as solvent burden, manufacturing yield, intra-particle geographic position of the API and excipients within the final parti- cle concept, particle morphology, surface energy of the particle, and anticipated aerosol characteristics as well as short term and long term stability. This topic is particu- larly relevant with regard to formulations that contain combination therapies and/or multiple excipients as actives and/or excipients may interact within the same spray dried particle. As highlighted in Figure 1, melt and glass transition tem- peratures, as well as organic solubility of API and excipi- ents, must be considered when creating a spray dried for- mulation, as these factors impact the ability to create par- ticles containing amorphous or crystalline drugs. 7, 8 Moreover, when considering excipients, manufacturers must evaluate solubility, function and chemical stability. Excipient addition must be a rational and flexible