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

Abstract

The recognition of hydroxyapatite (HAp) as the major bone mineral triggered significant research in bone tissue engineering applications. Although laboratoryscale 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 pilotscale 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.

Influence of pH in the synthesis of calcium phosphate based nanostructures with enhanced bioactivity and pro‐angiogenic properties

“…In the Raman spectrum Figure 2B, the vibrational band observed at 1135 cm −1 ascribes to the symmetric bending mode of v 1 CO 3 2− . The observed bands in the following ranges of 422, 562 — , and 1095 cm −1 correspond to v 2 symmetric bending, v 4 and v 3 asymmetric bending mode of PO 4 3− , respectively 32,33 …”

“…31 ) functional group. 32 The presence of CO group have been noticed between the range from 550 to 1120 cm À1 , and a minor depression at 630 cm À1 at H-CP is due to the physically absorbed hydroxyl ( À OH) group. 33 In the Raman spectrum Figure 2B, the vibrational band observed at 1135 cm À1 ascribes to the symmetric bending mode of v1 CO 3…”

“…From the spectrum, the widening and splitting of bands tend to sharpen has been observed by swapping the pH from acidic to alkaline. The bands observed at M‐CP in the wavenumbers of 549, 603, 992, 1059 — , and 1129 cm −1 corresponds to the bending mode of phosphate (PO 4 3− ) functional group 32 . The presence of CO 3 2− valley at 885 and 1348 cm −1 are considered to be integrated from ambience CO 2.…”

Osteochondral regenerative engineering: challenges, state-of-the-art and translational perspectives

“…trabecular architectures are also reported but to a comparatively lesser extent. Hydroxyapatite (HAp) is the major workhorse to model the subchondral bone alone or in combination with other polymeric biomaterials [ 58 ]. Apart from HAp, tricalcium phosphate (TCP), tetracalcium phosphate, biphasic calcium phosphate, Bioglass ® etc.…”