Non-destructive dose verification of two drugs within 3D printed polyprintlets.

Three-dimensional printing (3DP) is a revolutionary technology in pharmaceuticals, enabling the personalisation of flexible-dose drug products and 3D printed polypills (polyprintlets). A major barrier to entry of this technology is the lack of non-destructive quality control methods capable of verifying the dosage of multiple drugs in polyprintlets at the point of dispensing. In the present study, 3D printed films and cylindrical polyprintlets were loaded with flexible, therapeutic dosages of two distinct drugs (amlodipine and lisinopril) across concentration ranges of 1-5% w/w and 2-10% w/w, respectively. The polyprintlets were non-destructively analysed for dose content using a portable near infrared (NIR) spectrometer and validated calibration models were developed using partial least squares (PLS) regression, which showed excellent linearity (R2 Pred = 0.997, 0.991), accuracy (RMSEP= 0.24%, 0.24%) and specificity (LV1= 82.77%, 79.55%) for amlodipine and lisinopril, respectively. X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA) showed that sintering partially transformed the phase of both drugs from the crystalline to amorphous forms. For the first time, we report a non-destructive, RTR quality control of two separate active ingredients in a single 3D printed drug product using NIR spectroscopy, overcoming a major barrier to the integration of 3D printing into clinical practice.

[1]  J. Coburn,et al.  Additively manufactured medical products – the FDA perspective , 2016, 3D printing in medicine.

[2]  Christine M. Madla,et al.  Fabricating 3D printed orally disintegrating printlets using selective laser sintering. , 2018, International journal of pharmaceutics.

[3]  Alexander T Florence,et al.  Personalised medicines: more tailored drugs, more tailored delivery. , 2011, International journal of pharmaceutics.

[4]  Simon Gaisford,et al.  3D Printed Pellets (Miniprintlets): A Novel, Multi-Drug, Controlled Release Platform Technology , 2019, Pharmaceutics.

[5]  M. Videa,et al.  Stabilization of amorphous paracetamol based systems using traditional and novel strategies. , 2014, International journal of pharmaceutics.

[6]  Jukka Rantanen,et al.  Anti‐tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[7]  Waqar Ahmed,et al.  Emergence of 3D Printed Dosage Forms: Opportunities and Challenges , 2016, Pharmaceutical Research.

[8]  Orestis L. Katsamenis,et al.  A 3D printed bilayer oral solid dosage form combining metformin for prolonged and glimepiride for immediate drug delivery , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[9]  H. Lee,et al.  Effect of adherence to antihypertensive medication on stroke incidence in patients with hypertension: a population-based retrospective cohort study , 2017, BMJ Open.

[10]  Abdullah Isreb,et al.  ‘Temporary Plasticiser’: A novel solution to fabricate 3D printed patient‐centred cardiovascular ‘Polypill’ architectures , 2019, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[11]  Simon Gaisford,et al.  3D Printing of a Multi-Layered Polypill Containing Six Drugs Using a Novel Stereolithographic Method , 2019, Pharmaceutics.

[12]  V. Castaño,et al.  Degradation of lisinopril: A physico-chemical study , 2008 .

[13]  Simon Gaisford,et al.  3D Printing Pharmaceuticals: Drug Development to Frontline Care. , 2018, Trends in pharmacological sciences.

[14]  K. Bhatt,et al.  Simultaneous Estimation of Amlodipine Besylate and Indapamide in a Pharmaceutical Formulation by a High Performance Liquid Chromatographic (RP-HPLC) Method , 2012, Scientia pharmaceutica.

[15]  M. Kivimäki,et al.  Adherence to antihypertensive therapy prior to the first presentation of stroke in hypertensive adults: population-based study. , 2013, European heart journal.

[16]  Waqar Ahmed,et al.  Adaptation of pharmaceutical excipients to FDM 3D printing for the fabrication of patient-tailored immediate release tablets. , 2016, International journal of pharmaceutics.

[17]  Waqar Ahmed,et al.  Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[18]  N. Sandler,et al.  Application of a handheld NIR spectrometer in prediction of drug content in inkjet printed orodispersible formulations containing prednisolone and levothyroxine. , 2017, International journal of pharmaceutics.

[19]  M. Alexander,et al.  3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[20]  Maren Preis,et al.  3D-Printed Isoniazid Tablets for the Treatment and Prevention of Tuberculosis—Personalized Dosing and Drug Release , 2019, AAPS PharmSciTech.

[21]  Ashwini Nangia,et al.  Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals , 2011 .

[22]  M. Jamrógiewicz Application of the near-infrared spectroscopy in the pharmaceutical technology. , 2012, Journal of pharmaceutical and biomedical analysis.

[23]  Simon Gaisford,et al.  Reshaping drug development using 3D printing. , 2018, Drug discovery today.

[24]  Sarah J Trenfield,et al.  Formulation, Analytical, and Regulatory Strategies for First‐in‐Human Clinical Trials , 2017 .

[25]  Abdul W. Basit,et al.  Patient acceptability of 3D printed medicines. , 2017, International journal of pharmaceutics.

[26]  L. Bulto,et al.  Adherence to prescribed antihypertensive medications and associated factors for hypertensive patients attending chronic follow-up units of selected public hospitals in Addis Ababa, Ethiopia , 2017, International journal of health sciences.

[28]  C. Lau,et al.  Prevalence, Awareness, Treatment, and Control of Hypertension Among United States Adults 1999–2004 , 2007, Hypertension.

[29]  Simon Gaisford,et al.  3D printed drug products: Non‐destructive dose verification using a rapid point‐and‐shoot approach , 2018, International journal of pharmaceutics.

[30]  A. Basit,et al.  3D Printing of Pharmaceuticals , 2018, AAPS Advances in the Pharmaceutical Sciences Series.

[31]  Simon Gaisford,et al.  3D printed medicines: A new branch of digital healthcare , 2018, International journal of pharmaceutics.

[32]  F. Collins,et al.  The path to personalized medicine. , 2010, The New England journal of medicine.

[33]  R. Modolo,et al.  A practical approach for measurement of antihypertensive medication adherence in patients with resistant hypertension. , 2016, Journal of the American Society of Hypertension : JASH.

[34]  Simon Gaisford,et al.  Selective laser sintering (SLS) 3D printing of medicines. , 2017, International journal of pharmaceutics.

[35]  M. Alexander,et al.  3D printing of tablets containing multiple drugs with defined release profiles. , 2015, International journal of pharmaceutics.

[36]  Y. Roggo,et al.  A review of near infrared spectroscopy and chemometrics in pharmaceutical technologies. , 2007, Journal of pharmaceutical and biomedical analysis.

[37]  Simon Gaisford,et al.  Direct powder extrusion 3D printing: Fabrication of drug products using a novel single-step process. , 2019, International journal of pharmaceutics.

[38]  G. Betz,et al.  Assessment of diffuse transmission mode in near-infrared quantification--part I: The press effect on low-dose pharmaceutical tablets. , 2009, Journal of pharmaceutical sciences.

[39]  Pamela Robles Martinez,et al.  Influence of Geometry on the Drug Release Profiles of Stereolithographic (SLA) 3D-Printed Tablets , 2018, AAPS PharmSciTech.

[40]  Yves Roggo,et al.  Near-infrared determination of active substance content in intact low-dosage tablets. , 2005, Talanta.

[41]  Abdul W. Basit,et al.  Stereolithography (SLA) 3D printing of an antihypertensive polyprintlet: Case study of an unexpected photopolymer-drug reaction , 2020 .

[42]  Peter Timmins,et al.  From ‘fixed dose combinations’ to ‘a dynamic dose combiner’: 3D printed bi‐layer antihypertensive tablets , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[43]  A. Roy,et al.  Strengths and Limitations of Using the Polypill in Cardiovascular Prevention , 2017, Current Cardiology Reports.

[44]  Simon Gaisford,et al.  Track-and-trace: Novel anti-counterfeit measures for 3D printed personalized drug products using smart material inks. , 2019, International journal of pharmaceutics.

[45]  A. Savitzky,et al.  Smoothing and Differentiation of Data by Simplified Least Squares Procedures. , 1964 .

[46]  L. Ruilope Current challenges in the clinical management of hypertension , 2012, Nature Reviews Cardiology.

[47]  Abdul W. Basit,et al.  Printing T3 and T4 oral drug combinations as a novel strategy for hypothyroidism , 2018, International journal of pharmaceutics.

[48]  Abdul W. Basit,et al.  3D printing of drug‐loaded gyroid lattices using selective laser sintering , 2018, International journal of pharmaceutics.

[49]  Abdul W. Basit,et al.  Low temperature fused deposition modeling (FDM) 3D printing of thermolabile drugs , 2018, International journal of pharmaceutics.

[50]  A. Basit,et al.  Effect of geometry on drug release from 3D printed tablets. , 2015, International journal of pharmaceutics.

[51]  Jukka Rantanen,et al.  Analytical aspects of printed oral dosage forms , 2018, International journal of pharmaceutics.

[52]  Abdul W. Basit,et al.  Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: first single-centre, prospective, crossover study in patients. , 2019, International journal of pharmaceutics.

[53]  A. Basit,et al.  3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[54]  M. Khan,et al.  Understanding the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering 3D printing. , 2019, International journal of pharmaceutics.

[55]  Christine M. Madla,et al.  Shaping the future: recent advances of 3D printing in drug delivery and healthcare , 2019, Expert opinion on drug delivery.

[56]  R. Bro,et al.  Near-infrared chemical imaging (NIR-CI) on pharmaceutical solid dosage forms-comparing common calibration approaches. , 2008, Journal of pharmaceutical and biomedical analysis.