Pilot-scale manufacturing of phase-pure and highly crystalline hydroxyapatite: Lessons learned and process protocols

The recognition of hydroxyapatite (HAp) as the major bone mineral triggered significant research in bone tissue engineering applications. Although laboratory-scale development involves the synthesis of HAp in different routes, scalability with uncompromised quality remains a major challenge. This article reports a large-scale wet precipitation-based synthesis of phase-pure HAp using indigenously customized stirred tank reactors. The different synthesis parameters, like pH, reaction time, stirring rate, precursor addition, were tailored, together with the post-synthesis mechano-chemical treatment (aging induced Ostwald ripening) and calcinations, as the technology is matured to manufacture HAp powders in large volume. At least three batches of HAp were produced in the pilot-scale reactor with reproducible values of phase purity, compositional fingerprint, particle size distribution, flowability, etc. The post-calcination bluish tint was strategically addressed by adopting a proprietary calcination protocol. This batch process can produce around 200 kg/month of phase-pure and highly crystalline (91–94%) HAp using stirred tank reactors of different working volumes. Extensive scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses reveal the particle size of as-synthesized HAp powders with hexagonal crystal structure in the range of 20.47 ± 4.95 nm , while individual crystallite size in range of 22.3 ± 3.2 nm (XRD based Debye-Scherrer analysis). TEM-based SADP analysis confirms the highly crystalline hexagonal structure of as-synthesized HAp. The spray-dried powders with spherical shape having narrow size distribution (35–40 μm) could also be manufactured in large batches. The spray-dried HAp powders could be coated on clinically used stainless steel femoral stem implants using atmospheric plasma spray coating technique.