A case study on decentralized manufacturing of 3D printed medicines.

Pharmaceutical 3D printing (3DP) is one of the emerging enabling technologies of personalised medicines as it affords the ability to fabricate highly versatile dosage forms. In the past 2 years, national medicines regulatory authorities have held consultations with external stakeholders to adapt regulatory frameworks to embrace point-of-care manufacturing. The proposed concept of decentralized manufacturing (DM) involves the provision of feedstock intermediates (pharma-inks) prepared by pharmaceutical companies to DM sites for manufacturing into the final medicine. In this study, we examine the feasibility of this model, with respect to both manufacturing and quality control. Efavirenz-loaded granulates (0-35%w/w) were produced by a manufacturing partner and shipped to a 3DP site in a different country. Direct powder extrusion (DPE) 3DP was subsequently used to prepare printlets (3D printed tablets), with mass ranging 266-371 mg. All printlets released more than 80% drug load within the first 60 min of the in vitro drug release test. An in-line near-infrared spectroscopy system was used as a process analytical technology (PAT) to quantify the printlets' drug load. Calibration models were developed using partial least squares regression, which showed excellent linearity (R2 = 0.9833) and accuracy (RMSE = 1.0662). Overall, this work is the first to report the use of an in-line NIR system to perform real-time analysis of printlets prepared using pharma-inks produced by a pharmaceutical company. By demonstrating the feasibility of the proposed distribution model through this proof-of-concept study, this work paves the way for investigation of further PAT tools for quality control in 3DP point-of-care manufacturing.

In vitro-in vivo relationship for amorphous solid dispersions using a double membrane dissolution-permeation setup.

The use of amorphous solid dispersions (ASDs) is one commonly applied formulation strategy to improve the oral bioavailability of poorly water-soluble drugs by overcoming dissolution rate and/or solubility limitations. While bioavailability enhancement of ASDs is well documented, it has often been a challenge to establish a predictive model describing in vitro-in vivo relationship (IVIVR). In this study, it is hypothesized that drug absorption might be overestimated by in vitro dissolution-permeation (D/P)-setups, when drug in suspension has the possibility of directly interacting with the permeation barrier. This is supported by the overprediction of drug absorption from neat crystalline efavirenz compared to four ASDs in a D/P-setup based on the parallel artificial membrane permeability assay (PAMPA). However, linear IVIVR (R2 = 0.97) is established in a modified D/P-setup in which the addition of a hydrophilic PVDF-filter acts as a physical boundary between the donor compartment and the PAMPA-membrane. Based on microscopic visualization, the improved predictability of the modified D/P-setup is due to the avoidance of direct dissolution of drug particles in the lipid components of the PAMPA-membrane. In general, this principle might aid in providing a more reliable evaluation of formulations of poorly water-soluble drugs before initiating animal models.

Stability and intrinsic dissolution of vacuum compression molded amorphous solid dispersions of efavirenz.

In this study, the stability and intrinsic dissolution of vacuum compression molded (VCM) amorphous solid dispersions (ASDs) of efavirenz (EFV) were investigated in relation to its solubility limits in seven polymers determined by the melting point depression (MPD) method. The extrapolated solubility limits of EFV at 22 °C ranged from 3 to 68% (w/w) with PVOH being the only polymer suggesting immiscibility with EFV according to both MPD and Hansen solubility parameters (HSPs). All ASDs with EFV loadings below or close to their calculated solubility limit did not show any signs of crystallization upon conditioning for 7 months at either 22 or 37 °C and 23 or 75% relative humidity. However, all ASDs with EFV loading above the solubility limit crystallized at high humidity, while the ASDs with cellulose derived carrier polymers proved kinetically stable at low humidity over 7 months. While the EFV intrinsic dissolution rates from the VCM ASDs were partly depending on the polymer dissolution rate, no correlation was observed between EFV matrix crystallization and its miscibility in the polymer. Altogether, the observations of the study underline the importance of combining preformulation miscibility determination and dissolution studies to rationally decide on both stability and viability of ASD formulations.

Selective Laser Sintering 3D Printing of Orally Disintegrating Printlets Containing Ondansetron.

The aim of this work was to explore the feasibility of using selective laser sintering (SLS) 3D printing (3DP) to fabricate orodispersable printlets (ODPs) containing ondansetron. Ondansetron was first incorporated into drug-cyclodextrin complexes and then combined with the filler mannitol. Two 3D printed formulations with different levels of mannitol were prepared and tested, and a commercial ondansetron orally disintegrating tablet (ODT) product (Vonau® Flash) was also investigated for comparison. Both 3D printed formulations disintegrated at ~15 s and released more than 90% of the drug within 5 min independent of the mannitol content; these results were comparable to those obtained with the commercial product. This work demonstrates the potential of SLS 3DP to fabricate orodispersible printlets with characteristics similar to a commercial ODT, but with the added benefit of using a manufacturing technology able to prepare medicines individualized to the patient.

sp carbon chains surrounded by sp(3) carbon double helices: coordination-driven self-assembly of wirelike Pt(CC)(n)Pt moieties that are spanned by two P(CH(2))(m)P linkages.

Reactions of trans,trans-(C6F5)(p-tol3P)2Pt(CC)4Pt(Pp-tol3)2(C6F5) and diphosphines Ar2P(CH2)mPAr2 yield trans,trans-(C6F5)(Ar2P(CH2)mPAr2)Pt(CC)4Pt(Ar2P(CH2)mPAr2)(C6F5), in which the platinum atoms are spanned via an sp and two sp3 carbon chains (Ar/m = 3, Ph/14, 87%; 4, p-tol/14, 91%; 5, p-C6H4-t-Bu/14, 77%; 7, Ph/10, 80%; 8, Ph/11, 80%; 9, Ph/12, 36%; only oligomers form for m > 14). Crystal structures of 3-5 show that the sp3 chains adopt chiral double-helical conformations that shield the sp chain at approximately the van der Waals distance, with both enantiomers in the unit cell. The platinum square planes define angles of 196.6 degrees -189.9 degrees or more than a half twist. Crystal structures of 7-9, which have shorter sp3 chains, exhibit nonhelical conformations. Reaction of the corresponding Pt(CC)6Pt complex and Ph2P(CH2)18PPh2 gives an analogous adduct (27%). The crystal structure shows two independent molecules, one helical and the other not. Low-temperature NMR data suggest that the enantiomeric helical conformations of 3-5 rapidly interconvert in solution. Cyclic voltammograms of 3-5 show more reversible oxidations than model compounds lacking bridging sp3 chains. These are the only double-helical molecules that do not feature bonding interactions between the helix strands, or covalent bonds to templates dispersed throughout the strands, or any type of encoding. The driving force for helix formation is analyzed.

sp carbon chains surrounded by sp(3) carbon double helices: directed syntheses of wirelike Pt(CC)(n)Pt moieties that are spanned by two P(CH(2))(m)P linkages via alkene metathesis.

Reactions of trans-(C6F5)(Ph2P(CH2)m'CH=CH2)2PtCl (1; m' = a, 6; b, 7; c, 8; d, 9; e, 10) and H(CC)2H (HNEt2, cat. CuI) give trans-(C6F5)(Ph2P(CH2)m'CH=CH2)2Pt(CC)2H (3a-e, 80-95%). Oxidative homocouplings of 3a-d under Hay conditions (O2, cat. CuCl/TMEDA, acetone) yield trans,trans-(C6F5)(Ph2P(CH2)m'CH=CH2)2Pt(CC)4Pt(Ph2P(CH2)m'CH=CH2)2(C6F5) (4a-d, 64-84%). Treatment of 3c-e with excess HCCSiEt3 under Hay conditions gives trans-(C6F5)(Ph2P(CH2)m'CH=CH2)2Pt(CC)3SiEt3 (56-73%). Homocouplings (n-Bu4N+ F-, Me3SiCl, Hay conditions) afford trans,trans-(C6F5)(Ph2P(CH2)m'CH=CH2)2Pt(CC)6Pt(Ph2P(CH2)m'CH=CH2)2(C6F5) (13c-e, 59-64%). Reactions of 4a-d and 13c-e with Grubbs' catalyst, followed by hydrogenation, give mixtures of trans,trans-(C6F5)(Ph2P(CH2)mPPh2)Pt(CC)nPt(Ph2P(CH2)mPPh2)(C6F5) with termini-spanning diphosphines and trans,trans-(C6F5)(Ph2P(CH2)mPPh2)Pt(CC)nPt(Ph2P(CH2)mPPh2)(C6F5) with trans-spanning diphosphines (m = 2m' + 2; n = 4, 6). The latter (n = 4) are independently synthesized by similar metatheses/hydrogenations of 1a-d to give trans-(C6F5)(Ph2P(CH2)mPPh2)PtCl (49-59%), followed by analogous introductions of (CC)4 chains (66-77%). Crystal structures of complexes with termini-spanning diphosphines show sp3 chains with both double-helical (m/n = 20/4) and nonhelical (m/n = 20/6) conformations, and highly shielded sp chains. The sp3 chains of complexes with trans-spanning diphosphines exhibit double half-clamshell conformations. The dynamic properties of both classes of molecules are analyzed in detail.

The influence of oral L-arginine on fracture healing: an animal study.

BACKGROUND: The known biological activities of nitric oxide suggest a role in bone healing. We hypothesized that L-arginine, a source of nitric oxide, expedites the healing process of stabilized diaphyseal defects. TYPE OF STUDY: Prospective blinded animal study. METHODS: Using a guinea-pig model, a 7 mm diaphyseal and periosteal defect was produced in the right femur and splinted intramedullary with a 1.4 mm K-wire. The guinea pigs (n = 44) were treated orally in three parallel groups: two treatment groups received high doses of L-arginine (one group for 2 weeks and the other for 4 weeks) and a control group received vehicle only. After four weeks, all animals were killed and both femora explanted. Radiological, histological, histomorphometric and mechanical evaluation was performed blinded. RESULTS: Radiographs showed significantly more healing in the treatment groups (2 weeks, 10/15; 4 weeks, 11/15) than in the control group (3/14). The mechanical energy necessary for femur failure was significantly higher in the 4-week treatment group than in the control group (P < 0.05). Histology and histomorphometry showed significantly increased coverage of nonvascularized bone fragments with newly formed bone in the treatment groups (P < or = 0.05). The contralateral uninjured femora did not show significant differences between groups. CONCLUSIONS: Oral L-arginine expedites healing in stabilized diaphyseal defects in guinea pigs without detrimentally affecting uninjured counterparts.

Synthesis, structure, and reactivity of sp carbon chains with bis(phosphine) pentafluorophenylplatinum endgroups: butadiynediyl (C4) through hexadecaoctaynediyl (C16) bridges, and beyond.

The reaction of trans-[(C(6)F(5))(p-tol(3)P)(2)PtCl] (PtCl) and butadiyne (cat. CuI, HNEt(2)) gives trans-[(C(6)F(5))(p-tol(3)P)(2)Pt(Ctbond;C)(2)H] (PtC(4)H, 81 %), which reacts with excess HC(triple bond)CSiEt(3) under Hay coupling conditions (O(2), cat. CuCl/TMEDA, acetone) to yield PtC(6)Si (53 %). A solution of PtC(6)Si in acetone is treated with wet nBu(4)NF to generate PtC(6)H. The addition of ClSiMe(3) (F(-) scavenger) and then excess HC(triple bond)CSiEt(3) under Hay conditions gives PtC(8)Si (39 %). Hay homocouplings of PtC(4)H, PtC(6)H, and PtC(8)H (generated in situ analogously to PtC(6)H) yield PtC(8)Pt, PtC(12)Pt, and PtC(16)Pt (97-92 %). Reactions of PtC(4)H and PtC(6)H with PtCl (cat. CuCl, HNEt(2)) give PtC(4)Pt and PtC(6)Pt (69 %, 34 %). The attempted conversion of PtC(8)H to PtC(10)Si affords mainly PtC(16)Pt, with traces of PtC(20)Pt and PtC(24)Pt. The complexes PtC(x)Pt are exceedingly stable (dec pts 234 to 288 degrees C), and Et(3)P displaces p-tol(3)P to give the corresponding compounds Pt'C(8)Pt' and Pt'C(12)Pt' (94-90 %). The effect of carbon chain lengths upon IR nu(C(triple bond)C) patterns (progressively more bands), UV/Vis spectra (progressively red-shifted and more intense bands with epsilon >600 000 M(-1) cm(-1)), redox properties (progressively more difficult and less reversible oxidations), and NMR values are studied, and analyzed with respect to the polymeric sp carbon allotrope "carbyne". The crystal structure of PtC(12)Pt shows a dramatic, unprecedented degree of chain bending, whereas the chains in PtC(8)Pt, Pt'C(12)Pt', and PtC(16)Pt are nearly linear.